Dehalogeno compounds

ABSTRACT

3-(1-Aminocycloalkyl)pyrrolidinyl-substituted-6-dehalodeno(hydrogen-substituted)quinolon carboxylic acid derivatives having specific substitunets as represented by the following formula (I), its salts, and hydrates thereof exhibit a broad and potent antibacterial activity on gram-negative and gram-positive bacteria, in particular, resistant bacteria typified by gram-positive cocci, including MRSA, PRSP and VRE. Thus these compounds are usable as drugs.

TECHNICAL FIELD

[0001] This invention relates to a synthetic quinolone antibacterialagent which is useful as medicaments, veterinary drugs, drugs forfishery use, or antibacterial preservatives.

BACKGROUND ART

[0002] Since the discovery of norfloxacin, synthetic quinoloneantibacterial agents have been improved in antibacterial activity andpharmacokinetics, and many compounds are now used in the clinical filedas chemotherapeutic agents which are effective for in almost systemicinfectious diseases.

[0003] In recent years, generation of bacteria having low sensitivity tosynthetic quinolone antibacterial agents have been increasing inclinical situations. For example, like the case of Staphylococcus aureus(MRSA) and Streptococcus pneumococcus (PRSP) which are insusceptible toβ-lactam antibiotics and Enterococcus (VRE) which is insusceptible toaminoglycoside antibacterial agents, a case has been increasing in whicha gram-positive bacteria originally resistant to drugs other thansynthetic quinolone antibacterial agents also became low sensitive tosynthetic quinolone antibacterial agents. In consequence, syntheticquinolone antibacterial agents having higher efficacy are thus beingdemanded in clinical situations.

[0004] With regard to the side effects of synthetic quinoloneantibacterial agents, in addition to the central nervous systemstimulation effect, which has been a problem since priorly, theinduction of convulsion resulting from combined use with nonsteroidalanti-inflammatory agents, phototoxicity, etc. have also become known,and the development of synthetic quinolone antibacterial agents havinghigher safety is thus also being demanded.

[0005] It is known that the structure of the substituents at the7-position and 1-position (or positions corresponding to thesepositions; the same shall apply hereinafter) have a large influence onthe antibacterial activity, pharmacokinetics, and safety of syntheticquinolone antibacterial agents.

[0006] Quinolone derivatives, having a pyrrolidinyl group having anaminomethyl group at the 3-position, as the substituent at the7-position of the quinolone mother skeleton, are known to exhibit strongantibacterial activity against gram-negative and gram-positive bacteria.For example, there are 7-[3-(1-aminomethyl)pyrrolidin-1-yl]quinolonecarboxylic acid derivatives [Journal of Medicinal Chemistry, vol. 29, p.445 (1986)].

[0007] Furthermore, known examples of quinolone carboxylic acidderivatives having a substituent on the carbon atom of the aminomethylgroup of the 3-(1-aminomethyl)pyrrolidin-1-yl group include7-[3-(1-aminoethyl)pyrrolidin-1-yl]quinolone carboxylic acid derivatives[Journal of Medicinal Chemistry, vol. 36, p. 871 (1993)];7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl]quinolone carboxylic acidderivatives [Journal of Medicinal Chemistry, vol. 37, p. 733 (1994)];and 7-[3-(1-aminoalkyl)pyrrolidin-1-yl]quinolone carboxylic acidderivatives [Chemical and Pharmaceutical Bulletin, vol. 42, p. 1442(1994)], etc.

[0008] However, though the abovementioned quinolone derivatives, havinga 3-(aminomethyl)pyrrolidin-1-yl group, a3-(1-aminoethyl)pyrrolidin-1-yl group, or a group having a structuresimilar to these as a substituent, are compounds which exhibit strongantibacterial activity, it has been found that due to the low selectivetoxicity [see for example, Journal of Antimicrobial Chemotherapy, vol.33, p. 685 (1994)], these compounds act not only on bacteria but also onthe cells of eukaryotic organisms, and they are difficult to use asmedical drugs or as veterinary drugs. Therefore, quinolone compoundshaving these substituents have not been put to actual clinical use upuntil now.

[0009] Meanwhile, quinolone carboxylic acid derivatives, which have a3-(1-aminocycloalkyl)pyrrolidin-1-yl group as a substituent and arerelevant to the present invention, have been described in the form ofabroad concept in PCT/JP96/00208, which provides a description ofcompounds with the structure shown in formula A or formula B. That is,with a quinolone compound of formula A, the substituent (X¹) at the6-position is defined as being a halogen atom or a hydrogen atom.However, only quinolone carboxylic acids wherein the fluorine atom orother halogen atom is the substituent at the 6-position are disclosedspecifically in the abovementioned patent application. Therefore,PCT/JP96/00208 does not provide a specific description concerningquinolone carboxylic acids wherein hydrogen is substituted at the6-position. Furthermore, this publication does not provide any specificdisclosure as embodiments of3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-hydrogen-substituted-quinolonecarboxylic acids, wherein the present invention is concerned.

[0010] [In the above formula A, X¹ represents a halogen atom or ahydrogen atom and X² represents a halogen atom. (The definitions of thesubstituents in the compound shown in formula A are those given inPCT/JP96/00208 and are irrelevant to the definitions of substituents ofthe present invention even when the same symbols are used.)]

[0011] In the above formula A, R² is represented by formula B:

[0012] [In the above formula B, p represents an integer from 1 to 3, qrepresents an integer from 1 to 3, R⁹ represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms, R¹⁰ represents a hydrogen atom,an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6carbon atoms that has a hydroxyl group, or an alkyl group having 1 to 6carbon atoms that has a halogen atom. (The definitions of thesubstituents in the compound shown in formula B are those given inPCT/JP96/00208 and are irrelevant to the definitions of substituents ofthe present invention even when the same symbols are used.)]

[0013] Besides the above, an example of a literature that indicates aquinolone carboxylic acid derivative, which has a3-(1-aminocycloalkyl)pyrrolidin-1-yl group and is relevant to thepresent invention, is Chemical and Pharmaceutical Bulletin, vol. 42, p.1442 (1994). However, this literature does not contain any descriptionwhatsoever concerning3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-hydrogen-substituted-quinolonecarboxylic acids, which are compounds of the present invention.

[0014] Furthermore, for example, PCT/WO99/14214 indicates a6-hydrogen-substituted-quinolone carboxylic acid derivative, in which anitrogen-containing heterocyclic substituent, for example, the3-(1-aminoethyl)pyrrolidin-1-yl group, is introduced via acarbon-nitrogen bond into the 7-position of the quinolone skeleton andwhich is relevant to this invention. This application describescompounds represented by the formulas C and D. However, this applicationdoes not contain any description whatsoever concerning a3-(1-aminocycloalkyl)pyrrolidin-1-yl group, which is relevant to thepresent invention, as a substituent at the 7-position of the quinoloneskeleton shown in formula C. Furthermore, this application does notcontain any description whatsoever concerning3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-hydrogen-substituted-quinolonecarboxylic acids, which are relevant to the present invention and havethe above-mentioned group as a substituent.

[0015] [In the above formula C, R1 represents a cyclic alkyl grouphaving 3 to 6 carbon atoms, an alkyl group having 1 or 2 carbon atoms, astraight-chain alkenyl group having 2 to 3 carbon atoms, or abranched-chain alkyl group or alkenyl group having 3 to 4 carbon atoms,this alkyl group or cyclic alkyl group may be unsubstituted or the alkylgroup or cyclic alkyl group may be substituted by 1 to 3 fluorine atomsor by a phenyl group which is unsubstituted or is substituted by 1 to 3fluorine atoms or is substituted at the 4-position by a single hydroxylgroup, R6 represents a hydrogen atom, a hydroxyl group, an aminocarbonylgroup, a bromine atom, a cyano group, an alkyl group having 1 or 2carbon atoms, or an alkenyl group or alkynyl group having 2 to 4 carbonatoms, and this alkyl group may be unsubstituted or the alkyl group maybe substituted by a methyl group or an ethyl group that is unsubstitutedor is substituted by 1 to 3 fluorine atoms or one hydroxyl group oramino group. (The definitions of the substituents in the compound shownin formula C are those given in PCT/WO99/14214 and are irrelevant to thedefinitions of substituents of the present invention even when the samesymbols are used.)]

[0016] In the above formula, X is represented by formula D:

[0017] [In the above formula D, R7 represents an amino group, which isbonded to a carbon that is not adjacent the nitrogen atom of thepyrrolidine ring and may be unsubstituted or substituted by one or twoalkyl groups with 1 to 3 carbon atoms, or an aminoalkyl group, which isbonded to a carbon on the pyrrolidine ring and may be unsubstituted orsubstituted by an alkyl group having 1 to 3 carbon atoms, R9 representsa group selected from among the group comprised of a hydrogen atom, analkyl group having 1 to 4 carbon atoms, an alkenyl group and alkynylgroup having 2 to 6 carbon atoms, and fused and spiroalkyl group having3 to 6 carbon atoms, the alkyl group portions of these groups maybeunsubstituted or substituted by 1 to 3 fluorine atoms, and theabovementioned substituents R7 and R9 may be integrated to form a fusedor Spiro type ring structure with the pyrrolidine ring, with this fusedor spirocyclic part being formed from 2 to 5 carbon atoms and 0 or 1nitrogen atom. (The definitions of the substituents in the compoundshown in formula D are those given in PCT/WO99/14214 and are irrelevantto the definitions of substituents of the present invention even whenthe same symbols are used.)]

[0018] Other examples of literature that indicate6-hydrogen-substituted-quinolone carboxylic acid derivatives, which arerelevant to the present invention, include Journal of MedicinalChemistry, vol. 39, p. 4952 (1996). However, even this literature doesnot contain any description whatsoever concerning3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-hydrogen-substituted-quinolonecarboxylic acids, which are the compounds of the present invention.

DISCLOSURE OF THE INVENTION

[0019] The present inventors have conducted intensive studies to obtainquinolone compounds, which are excellent in antibacterial activity, highin efficacy, and yet excellent in safety. As a result, it has been foundthat3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-dehalogeno(hydrogen-substituted)quinolonecarboxylic acid derivatives represented by formula (I) described below,its salts and hydrates thereof exhibit potent antibacterial activityupon a broad range of gram-negative bacteria and gram-positive bacteriaand, in particular, exhibit potent antibacterial activity againstdrug-resistant bacteria, as represented by gram-positive cocci,including MRSA, PRSP, and VRE.

[0020] Furthermore, it has been found that, in addition to exhibitingsuch excellent antibacterial activity, the compounds of this inventionare excellent both in terms of safety and pharmacokinetics and thusenable use in clinical situations, which could not be achieved withcompounds prior to this invention which have substituents of the samestructure at the 7-position of the quinolone mother skeleton. Thepresent invention has been achieved based on these findings.

[0021] A comparison of the 6-hydrogen-substituted-quinolone carboxylicacid derivatives represented by formula (I), its salts and hydratesthereof according to the present invention with quinolone compoundswherein the hydrogen at the 6-position of a compound of this inventionis substituted by a fluorine atom shows that both types of compoundsexhibit excellent antibacterial activity upon a broad range of bothgram-negative bacteria and gram-positive bacteria, includingdrug-resistant bacteria. However, it has been found unexpectedly thatthe 6-hydrogen-substituted-quinolone derivatives, which are thecompounds of this invention, are compounds that, in comparison to the6-fluorine-substituted-quinolone derivatives, are compounds of excellentsafety that are reduced in acute toxicity and significantly reduced inmicronuclus induction, and also exhibit good pharmacokinetics, such asimproved urinary recovery, etc.

[0022] That is, the present inventors have found that even a quinolonecompound, which has a 3-(1-aminocycloalkyl)pyrrolidin-1-yl group havinga cyclic alkyl group as a substituent on the methyl group of the3-(aminomethyl)pyrrolidin-1-yl group and which as has been mentionedabove is known to be low in selective toxicity, will unexpectedly be acompound with excellent selective toxicity and be a compound ofexcellent pharmacokinetics as long as it is a quinolone compound withthe structure of the present invention.

[0023] That is, the present invention concerns compounds represented bythe following general formula (I), its salts, and hydrates thereof:

[0024] [wherein R¹ represents an alkyl group having 1 to 6 carbon atoms,an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl grouphaving 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbonatoms, which may have a substituent, an aryl group, which may have asubstituent, a heteroaryl group, which may have a substituent, an alkoxygroup having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6carbon atoms;

[0025] R² represents an alkylthio group having 1 to 6 carbon atoms or ahydrogen atom,

[0026] wherein R² and the abovementioned R¹ may be integrated to form aring structure by incorporating a part of the mother skeleton, the thusformed ring may contain a sulfur atom as a ring-constituent atom, andthe ring may be substituted by an alkyl group having 1 to 6 carbonatoms, which may have a substituent;

[0027] R³ represents a phenylalkyl group composed of an alkylene grouphaving 1 to 6 carbon atoms and a phenyl group, an alkyl group having 1to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, ahydrogen atom, a phenyl group, an acetoxymethyl group, apivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, adimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a5-alkyl-2-oxo-1,3-dioxole-4-ylmethyl group, or a 3-acetoxy-2-oxobutylgroup;

[0028] R⁴ represents an alkyl group having 1 to 6 carbon atoms, analkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydrogenatom, an amino group, a hydroxyl group, a thiol group, or ahalogenomethyl group, and

[0029] among the above, the amino group may have one or moresubstituents selected from among the group consisting of an alkyl grouphaving 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms,and a formyl group;

[0030] A represents a nitrogen atom or a partial structure representedby formula (II):

[0031]  (wherein X represents an alkyl group having 1 to 6 carbon atoms,an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, ahydrogen atom, an amino group, a halogen atom, a cyano group, ahalogenomethyl group, or a halogenomethoxy group,

[0032] among the above, the amino group may have one ore moresubstituents selected from the group consisting of an alkyl group having1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and aformyl group,

[0033] wherein X¹ and the aforementioned R¹ may be integrated to form aring structure by incorporating a part of the mother skeleton, the thusformed ring may contain an oxygen atom, a nitrogen atom, or a sulfuratom as a ring constituent atom, and this ring may be substituted by analkyl group having 1 to 6 carbon atoms, which may have a substituent);

[0034] each of R⁵ and R⁶ independently represents an alkyl group having1 to 6 carbon atoms, a hydrogen atom, or a substituted carboxyl groupderived from an amino acid, dipeptide, or tripeptide,

[0035] wherein the alkyl group may have one ore more substituentsselected from the group consisting of an alkylthio group having 1 to 6carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydroxylgroup, and a halogen atom; and n represents an integer 1 or 2].

[0036] The present invention also relates to each of the following:

[0037] a compound of the above formula (I), its salts or hydratesthereof, wherein the compound of formula (I) is a stereochemically purecompound;

[0038] a compound of the formula (I), its salts or hydrates thereof,wherein n in the formula (I) is 1;

[0039] a compound of the formula (I), its salts or hydrates thereof,wherein R³ in the formula (I) is a hydrogen atom;

[0040] a compound of the formula (I), its salts or hydrates thereof,wherein R² in the formula (I) is a hydrogen atom;

[0041] a compound of the formula (I), its salts or hydrates thereof,wherein R⁴ in the formula (I) is a hydrogen atom;

[0042] a compound of the formula (I), its salts or hydrates thereof,wherein A in the formula (I) is a partial structure represented by theformula (II);

[0043] a compound of the formula (I), its salts or hydrates thereof,wherein X¹ in the formula (II) is a methoxy group, a methyl group,

[0044] a difluoromethoxy group, a fluorine atom, or a chlorine atom;

[0045] a compound of the formula (I), its salts or hydrates thereof,wherein X¹ in the formula (II) is a methoxy group or a methyl group;

[0046] a compound of the formula (I), its salts or hydrates thereof,wherein each of R⁵ and R⁶ in the formula (I) is a hydrogen atom;

[0047] a compound of the formula (I), its salts or hydrates thereof,wherein one of either R⁵ or R⁶ in the formula (I) is a hydrogen atom andthe other is a methyl group;

[0048] a compound of the formula (I), its salts or hydrates thereof,wherein one of either R⁵ or R⁶ in formula (I) is a hydrogen atom and theother is a substituted carboxyl group derived from an amino acid, adipeptide, or a tripeptide;

[0049] a compound of the formula (I), its salts or hydrates thereof,wherein each of the R⁵ and R⁶ in formula (I) is a combination of ahydrogen atom and a methyl group;

[0050] a compound of the formula (I), its salts or hydrates thereof,wherein R⁶ in formula (I) is a substituted carboxyl group derived froman amino acid, a dipeptide, or a tripeptide;

[0051] a compound of the formula (I), its salts or hydrates thereof,wherein the cyclic alkyl group having 3 to 6 carbon atoms, which mayhave a substituent, in R¹ is a halogenocyclopropyl group;

[0052] a compound of the formula (I), its salts or hydrates thereof,wherein the halogenocyclopropyl group is a 1,2-cis-2-halogenocyclopropylgroup;

[0053] a compound of the formula (I), its salts or hydrates thereof,wherein the halogenocyclopropyl group is a stereochemically puresubstituent;

[0054] a compound of the formula (I), its salts or hydrates thereof,wherein the halogenocyclopropyl group is a (1R,2S)-2-halogenocyclopropyl group;

[0055] a compound of the formula (I), its salts or hydrates thereof,wherein the halogen atom of the halogenocyclopropyl group is a fluorineatom;

[0056]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, its salts or hydrates thereof;

[0057]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0058]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0059]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0060]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0061]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0062]7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0063]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0064]7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0065]7-[3-(R)-[1-(ethylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0066]5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-fluoro-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0067]5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0068]5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0069]5-amino-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0070]10-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylicacid, its salts or hydrates thereof;

[0071]1-(cyclopropyl)-8-methyl-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof;

[0072] a medicament, which comprises a compound of formula (I), itssalts or hydrates thereof as an active ingredient;

[0073] an antibacterial agent, which comprises a compound of formula(I), its salts or hydrates thereof as an active ingredient;

[0074] a therapeutic agent for an infectious disease, which comprises acompound of the formula (I), its salts or hydrates thereof as an activeingredient;

[0075] a method for treating a disease, which comprises administrating acompound of the formula (I), its salts or hydrates thereof as an activeingredient;

[0076] a method for treating an infectious disease, which comprisesadministrating a compound of the formula (I), its salts or hydratesthereof as an active ingredient;

[0077] a method for producing a medicament, which comprises formulatinga compound of the formula (I), its salts or hydrates thereof as anactive ingredient;

[0078] a method for producing an antibacterial agent, which comprisesformulating a compound of the formula (I), its salts or hydrates thereofas an active ingredient;

[0079] a method for producing an infectious disease treating agent,which comprises formulating a compound of the formula (I), its salts orhydrates thereof as an active ingredient;

[0080] use of a compound of the formula (I), its salts or hydratesthereof for the production of a medicament;

[0081] use of a compound of the formula (I), its salts or hydratesthereof for the production of an antibacterial agent;

[0082] use of a compound of the formula (I), its salts or hydratesthereof for the production of an infectious disease treating agent;

[0083] and so on.

[0084] (Mode for Carrying out the Invention)

[0085] The various substituents of the compound of this inventionrepresented by formula (I):

[0086] (R¹, R², R³, R⁴, R⁵, R⁶, n and A are defined as has beendescribed above) shall now be described. (For the 6-position of thequinolone mother skeleton or an equivalent position in the structuralformulae indicated in the present specification, in order to stress thata hydrogen atom is bonded, the hydrogen atom that is bonded to a carbon,which is normally not indicated as customary in structural formulae inorganic chemistry, is indicated in some cases (in the form of “—H”).However, the structural formulae of this specification are indicated inline with the rules of indication of structural formulae that arenormally practiced in the field of organic chemistry, and a hydrogenatom that is bonded to a carbon atom will not always be indicated butwill normally be omitted.)

[0087] The substituent R¹ is an alkyl group having 1 to 6 carbon atoms,an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl grouphaving 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbonatoms, which may have a substituent, an aryl group, which may have asubstituent, a heteroaryl group, which may have a substituent, an alkoxygroup having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6carbon atoms.

[0088] Here, an alkyl group having 1 to 6 carbon atoms may be astraight-chain or branched-chain alkyl group, preferably an alkyl grouphaving 1 to 4 carbon atoms, more preferably an ethyl group. As analkenyl group having 2 to 6 carbon atoms, a vinyl group or a1-isopropenyl group is preferable. As a halogenoalkyl group having 1 to6 carbon atoms, a 2-fluoroethyl group is preferable. As a cyclic alkylgroup, a cyclopropyl group is especially preferable. The cyclic alkylgroup may have a substituent, and a halogen atom is preferable as thesubstituent. A halogenocyclopropyl group is preferable as the cyclicalkyl group, which may have a substituent, and a fluorine atom isespecially preferable as the halogen atom in this group. As ahalogenocyclopropyl group, a monohalogenocyclopropyl group is preferableand a cis-substituted group is even more preferable.

[0089] Examples of an aryl group, which may have a substituent, includea phenyl group, etc., which may have 1 to 3 substituents selected fromthe group consisting of an alkyl group having 1 to 6 carbon atoms, analkoxy group having 1 to 6 carbon atoms, a halogen atom such as fluorineatom, chlorine atom and bromine atom, a hydroxyl group, an amino group,a nitro group, etc. (in the case where the aryl group has a plurality ofsubstituents, the substituents may be of a single type or may be of aplurality of types). To be more specific, a phenyl group,a2-fluorophenyl group, a 4-fluorophenyl group, a 2,4-difluorophenylgroup, a 2-fluoro-4-hydroxyphenyl group, a 3-amino-4,6-difluorophenylgroup, and a 4,6-difluoro-3-methylaminophenyl group are preferable. Byaryl group, a group that is derived from an aromatic hydrocarboncompound is referred to. Besides the phenyl group, the aryl group mayalso be a naphthyl group or a tricyclic aryl group having more rings.

[0090] A heteroaryl group is a group that is derived from a pentacyclicor hexacyclic aromatic heterocyclic compound that contains one or morehetero atoms selected from among the nitrogen atom, oxygen atom, andsulfur atom. A pentacyclic or hexacyclic nitrogen-containingheterocyclic substituent that contains 1 or 2 nitrogen atoms isespecially preferable. For example, a pyridyl group, pyrimidyl group,etc are cired. An alkyl group, a halogen atom, etc. are preferable assubstituents on these rings. A 6-amino-3,5-difluoro-2-pyridyl group isespecially preferable.

[0091] As an alkoxy group having 1 to 6 carbon atoms, an alkoxy groupthat is derived from an abovementioned alkyl group is preferable andamong these, the methoxy group is preferable. For an alkylamino grouphaving 1 to 6 carbon atoms, the alkyl portion may be an abovementionedalkyl group. A methylamino group is preferable as the alkylamino group.

[0092] As the substituent R¹, a cyclic alkyl group or ahalogenocycloalkyl group is preferable. Among these, a cyclopropyl groupor a 2-halogenocyclopropyl group is preferable. As the halogen atom inthe 2-halogenocyclopropyl group, a fluorine atom is preferable.

[0093] The substituent R² represents an alkylthio group having 1 to 6carbon atoms or a hydrogen atom, and R¹ and R² may be integrated to forma ring structure comprised of a polymethylene chain by incorporating apart of the mother skeleton (that is, so as to contain the nitrogen atomto which R¹ is bonded and the carbon atom to which R² is bonded). Thethus formed ring may contain a sulfur atom as a ring constituent atom,and this ring may also have an alkyl group or halogenoalkyl group having1 to 6 carbon atoms as a substituent. The formed ring may be tetracyclicto hexacyclic in size and this ring may be also saturated orunsaturated. A methyl group or a fluoromethyl group is preferable as thesubstituent on the formed ring. Examples of the fused ring structureformed in this manner include the following:

[0094] (In the above formula, R⁷ represents an alkyl group having 1 to 6carbon atoms, such as a methyl group, a halogenoalkyl group having 1 to6 carbon atoms, such as a fluoromethyl group, or a hydrogen atom, and R⁸represents a halogen atom, such as a fluorine atom, or a hydrogen atom.)

[0095] A hydrogen atom is preferable as the substituent R² of thecompound of formula (I).

[0096] The substituent R³ is a phenylalkyl group (aralkyl group)composed of an alkylene group having 1 to 6 carbon atoms and a phenylgroup, or an alkyl group having 1 to 6 carbon atoms, an alkoxymethylgroup having 2 to 7 carbon atoms, a hydrogen atom, a phenyl group, anacetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group,a choline group, a dimethylaminoethyl group, a 5-indanyl group, aphthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxole-4-ylmethyl group, or a3-acetoxy-2-oxobutyl group.

[0097] In the case where a compound of this invention is to be used forantibacterial purposes, it is preferable to use a carboxylic acidcompound wherein R³ is a hydrogen atom. Meanwhile, a quinolonederivative wherein the carboxylic acid moiety has been made an ester isuseful as a synthesis intermediate or as a prodrug. These aspects shallbe described in more detail below.

[0098] R⁴ represents an alkyl group having 1 to 6 carbon atoms, analkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydrogenatom, an amino group, a hydroxyl group, a thiol group, or anhalogenomethyl group, and among the above, the amino group may have oneore more substituents selected from the group consisting of an alkylgroup having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbonatoms, and a formyl group. In the case where there are a plurality ofsubstituent groups, the substituents may all be of the same type or maybe of a plurality of different types.

[0099] As an alkyl group, which may either be a straight-chain orbranched-chain group having 1 to 6 carbon atoms, a methyl group, anethyl group, a normal propyl group, or an isopropyl group is preferable.As an alkenyl group, which may either be a straight-chain orbranched-chain group having 2 to 6 carbon atoms, a vinyl group ispreferable. As an alkynyl group, which may be a straight-chain orbranched-chain group having 2 to 6 carbon atoms, an ethynyl group ispreferable. As the halogen of a halogenomethyl group, a fluorine atom isespecially preferable and the number thereof may be 1 to 3. As an alkoxygroup, which may have 1 to 6 carbon atoms, a methoxy group ispreferable.

[0100] The substituent R⁴ is preferably a hydrogen atom, an alkyl group,or an amino group, and among these, a hydrogen atom, a methyl group, orunsubstituted amino group (—NH₂) is especially preferable.

[0101] In the case where R⁴ is an amino group, a hydroxyl group, or athiol group, it may be protected by a protective group that is normallyused in the relevant fields.

[0102] Examples of such protective groups include (substituted)alkoxycarbonyl groups, such as tert-butoxycarbonyl group,2,2,2-trichloroethoxycarbonyl group, etc.; (substituted)aralkyloxycarbonyl groups, such as benzyloxycarbonyl group,paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group,etc.; (substituted) acyl groups, such as acetyl group, methoxyacetylgroup, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formylgroup, benzoyl group, etc.; (substituted) alkyl groups or (substituted)aralkyl groups, such as tert-butyl group, benzyl group, paranitrobenzylgroup, paramethoxybenzyl group, triphenylmethyl group, etc.;(substituted) ethers, such as methoxymethyl group, tert-butoxymethylgroup, tetrahydropyranyl group, 2,2,2-trichloroethoxymethyl group, etc.;and (alkyl and/or aralkyl) substituted silyl groups, such astrimethylsilyl group, isopropyldimethylsilyl group,tert-butyldimethylsilyl group, tribenzylsilyl group,tert-butyldiphenylsilyl group, etc. (here, “(substituted)” signifiesthat a group may have a substituent). A compound having an amino group,hydroxyl group, or thiol group that is protected by such a substituentis especially preferable as a production intermediate.

[0103] A represents a nitrogen atom or a partial structure expressed byformula (II):

[0104] In the case where A is a partial structure of the formula (II),X¹ represents an alkyl group having 1 to 6 carbon atoms, an alkenylgroup having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbonatoms, an alkoxy group having 1 to 6 carbon atoms, a hydrogen atom, anamino group, a halogen atom, a cyano group, a halogenomethyl group, or ahalogenomethoxy group, and among the above, the amino group may have oneore more substituents selected from the group consisting of an alkylgroup having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbonatoms, and a formyl group.

[0105] As a halogen atom, a fluorine atom, a chlorine atom, and abromine atom are preferable and the fluorine atom and chlorine atom areespecially preferable. As an alkyl group, which may be a straight-chainor branched-chain group having 1 to 6 carbon atoms, a methyl group, anethyl group, a normal propyl group, or an isopropyl group is preferable.As an alkenyl group, which may either be a straight-chain orbranched-chain group having 2 to 6 carbon atoms, a vinyl group ispreferable. As an alkynyl group, which may be a straight-chain orbranched-chain group having 2 to 6 carbon atoms, an ethynyl group ispreferable. As the halogen of a halogenomethyl group, a fluorine atom isespecially preferable and the number thereof may be 1 to 3. As an alkoxygroup, which may have 1 to 6 carbon atoms, a methoxy group ispreferable. As the halogen of a halogenomethoxy group, a fluorine atomis especially preferable and the number thereof may be 1 to 3.

[0106] Among these substituents, an alkyl group or an alkoxy group ispreferable. A methyl group, an ethyl group, a methoxy group, or adifluoromethoxy group is especially preferable.

[0107] Further, this X¹ and the abovementioned R¹ may be integrated toform a ring structure comprised of a polymethylene ring by incorporatinga part of the mother skeleton (so as to contain the carbon atom to whichX¹ is bonded and the nitrogen atom to which R¹ is bonded). The thusformed ring may contain an oxygen atom, a nitrogen atom, or a sulfuratom as a ring constituent atom, and this ring may also have as asubstituent an alkyl group having 1 to 6 carbon atoms, which may have asubstituent in turn.

[0108] The formed ring may be pentacyclic to heptacyclic in size and thering constituent atoms are not limited to a carbon atom and may includean oxygen atom, a nitrogen atom, or a sulfur atom. Further, this ringmay be saturated or unsaturated. The thus formed ring may have an alkylgroup having 1 to 6 carbon atoms as a substituent. This alkyl group maybe considered to be the same as the above-described alkyl group and ispreferably a methyl group. This alkyl group may be substituted by ahalogen atom, an alkoxy group, etc.

[0109] As a partial structure that forms the ring structure formed by X¹and R¹, a structure of the following formula:

—O—CH₂—CH(—CH₃)—

[0110] is preferable (the right end of the above is bonded to a nitrogenatom), and especially, the quinolone skeleton of the following structureis preferable:

[0111] If A is a partial structure of formula (II), preferablecombinations of R⁴ and X¹ are those in which R⁴ is an alkyl group having1 to 6 carbon atoms, an amino group, a hydrogen atom, or a hydroxylgroup and X¹ is an alkyl group having 1 to 6 carbon atoms, an alkoxygroup 1 to 6 carbon atoms, a halogenomethoxy group, or a hydrogen atom.

[0112] More preferable combinations are those in which R⁴ is an aminogroup, a hydrogen atom, a hydroxyl group, or a methyl group and X¹ is amethyl group, a methoxy group, a difluoromethoxy group, or a hydrogenatom.

[0113] Especially preferable combinations are those in which R⁴ is ahydrogen atom, a hydroxyl group, or a methyl group and X¹ is a methylgroup or a methoxy group.

[0114] Each of substituent R⁵ and R⁶ independently represents an alkylgroup having 1 to 6 carbon atoms, a hydrogen atom, or a substitutedcarboxyl group derived from an amino acid, a dipeptide, or a tripeptide.

[0115] This alkyl group may have one ore more substituents selected fromthe group consisting of an alkylthio group having 1 to 6 carbon atoms,an alkoxy group having 1 to 6 carbon atoms, a hydroxyl group, and ahalogen atom.

[0116] As an alkyl group, which may either be a straight-chain orbranched-chain group having 1 to 6 carbon atoms, a methyl group, anethyl group, a normal propyl group, or an isopropyl group is preferable.

[0117] In the case where the alkyl group has a hydroxyl group as asubstituent, the alkyl group may be a straight-chain or branched-chaingroup having 1 to 6 carbon atoms, and the hydroxyl group is morepreferably substituted on the terminal carbon atom of the alkyl group.As an alkyl group having a hydroxyl group, those with up to 3 carbonatoms is preferable and a hydroxymethyl group, a 2-hydroxyethyl group, a2-hydroxypropyl group, a 3-hydroxypropyl group, etc. are preferable.

[0118] In the case where the alkyl group has a halogen atom as asubstituent, the alkyl group may be a straight-chain or branched-chaingroup having 1 to 6 carbon atoms, and the halogen atom is preferably afluorine atom. The number of fluorine atoms may correspond to amono-substituted condition to a perfluoro-substituted condition.Examples thereof include a monofluoromethyl group, a difluoromethylgroup, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, etc.

[0119] In the case where the alkyl group has an alkylthio group as asubstituent, the alkyl group may be a straight-chain or branched-chaingroup having 1 to 6 carbon atoms, and thealkylthio group may also be astraight-chain or branched-chain group having 1 to 6 carbon atoms. As analkyl group having an alkylthio group, an alkylthiomethyl group, analkylthioethyl group, or an alkylthiopropyl group is preferable and itis more preferable for the alkylthio group to be a group having 1 to 3carbon atoms as well. More preferable examples thereof include amethylthiomethyl group, an ethylthioethyl group, and a methylthioethylgroup.

[0120] In the case where the alkyl group has an alkoxy group as asubstituent, the alkyl group may be a straight-chain or branched-chaingroup having 1 to 6 carbon atoms, and the alkoxy group may also bestraight-chain or branched-chain group having 1 to 6 carbon atoms. As analkyl group having an alkoxy group, an alkoxymethyl group, analkoxyethyl group, or an alkoxypropyl group is preferable and it is morepreferable for the alkoxy group to be a group having up to 3 carbonatoms as well. More preferable examples thereof include a methoxymethylgroup, an ethoxymethyl group, and a methoxyethyl group.

[0121] Preferable combinations of R⁵ and R⁶ are those in which one is ahydrogen atom and the other is a hydrogen atom, an alkyl group, or asubstituted carboxyl group derived from an amino acid, a dipeptide, or atripeptide. Among these, a combination in which one of either R⁵ or R⁶is a hydrogen atom and the other is a hydrogen atom or an alkyl group ismore preferable. As an alkyl group, a methyl group or an ethyl group ispreferable and a methyl group is especially preferable. Thus, acombination in which both R⁵ and R⁶ are hydrogen atoms or a combinationin which one of either R⁵ or R⁶ is a hydrogen atom and the other is amethyl group is especially preferable. A compound of this combinationcan especially express favorable physiological activity as anantibacterial agent.

[0122] A quinolone derivative, wherein one of either substituent R⁵ orR⁶ is a hydrogen atom and the other is a substituted carboxyl groupderived from an amino acid, a dipeptide, or a tripeptide is especiallyuseful as a prodrug. Specific examples regarding this shall be describedbelow.

[0123] A description shall now be given concerning thehalogenocyclopropyl group of R¹.

[0124] The substituent halogen atom is preferably a fluorine atom or achlorine atom and a fluorine atom is especially preferable.

[0125] It is especially preferable for the stereochemical environment atthis moiety that the halogen atom and the quinolone carboxylic acidmoiety have cis-configuration on the cyclopropane ring. Also, though thecis-configuration substituent in this case may take the form of a2-(S)-halogeno-1-(R)-cyclopropyl group or a2-(R)-halogeno-1-(S)-cyclopropyl group, the former is preferable.

[0126] Though so-called enantiomorphic isomers are present due to thecis-2-halogenocyclopropyl moiety alone of R¹, all of such isomers havebeen found to be strong in antibacterial activity and high in safety.

[0127] A compound of this invention, exhibits excellent characteristicswhen there is a substituent of the structure represented by thefollowing formula E at the 7-position of a quinolone mother skeleton, inparticular, a1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid skeleton having a 2-(S)-halogeno-1-(R)-cyclopropyl group.

[0128] For this substituent, two optical isomers that are in anenantiomorphic relationship exist as a result of the asymmetric carbonatom at the 3-position of the pyrrolidine ring. To be more specific,these are as follows:

[0129] Meanwhile, the correlation of the structural activities of twotypes of optically active compounds that are due to the stericconfiguration of the substituent at the 7-position (or its equivalentposition) of a 7-[3-(1-aminomethyl)pyrrolidin-1-yl]quinolone carboxylicacid derivative and the correlation of the structural activities of fourtypes of optically active substances that are due to the stericconfiguration of the substituent at the 7-position of a7-[3-(1-aminoethyl)pyrrolidin-1-yl]quinolone carboxylic acid derivativeare described in Journal of Medicinal Chemistry, vol. 36, p. 1442(1994). In this literature, it is indicated that among these opticalisomers, the isomers of the structures shown in the following formulaare highest in antibacterial activity.

[0130] From the steric configurations at the 3-position of thesepyrrolidine rings, the present inventors considered that of the twooptical isomers shown in above formula F, the following isomer was morepreferable:

[0131] Thus, a more preferable compound of the compounds of thisinvention has the structure represented by the following formula:

[0132] That is, 3-(1-aminocycloalkyl)pyrrolidinylsubstituted-6-hydrogen-substituted-quinolone carboxylic acids,represented by formula (I), its salts, and hydrates thereof (especiallycompounds having the structure where the 3-position of the abovepyrrolidine ring is R-configuration, its salts, and hydrates thereof)exhibit potent antibacterial activity against a wide range ofgram-negative bacteria and gram-positive bacteria, and in particular, acharacteristic of these compounds of this invention is that they exhibitpotent antibacterial activity against resistant bacteria as representedby gram-positive cocci, including MRSA, PRSP, and VRE. In addition, thecharacteristics of the compounds of this invention are that they exhibitexcellent safety and good pharmacokinetics that enable the compounds tobe used inclinical situations, which could not be achieved withcompounds prior to this invention even if they had substituents of thesame structures.

[0133] Such excellent properties of the compounds of this invention areexhibited by compounds in which the n in the above-described substituentis an integer of 1 or 2, and the excellent effects are seen especiallywith compounds for which n is an integer 1. That is, compounds whereinthe cyclic part is a tricyclic ring are preferable compounds.

[0134] In the case where a compound of formula (I) of this invention hasa structure in which diastereomers are present, a compound comprised ofa single diastereomer is preferably administered when the compound ofthis invention is administered to human or animals. The term, “comprisedof a single diastereomer” as used herein means not only a case in whichit is completely free from the other diastereomer but also a case inwhich it is in a chemically pure degree. That is, it may be interpretedthat the other diastereomer may be contained as long as there are noinfluences on the physical constants and physiological activities of thecompound.

[0135] Also, the term “stereochemically pure” as used herein means that,in the case where a compound or the like exists in a plurality of isomerforms due to the bpresence of asymmetric carbon atoms, the compound iscomprised of only one of them. The term “pure” in this case can also beconsidered in the same manner as described above.

[0136] Though the quinolone carboxylic acid derivative of this inventionmay be used either in its free form or as an acid addition salt or asalt of its carboxyl group. Examples of the acid addition salt includeinorganic acid salts, such as hydrochlorides, sulfates, nitrates,hydrobromides, hydroiodides, phosphates, etc.; and organic acid salts,such as methanesulfonates, benzenesulfonates, toluenesulfonates (andother sulfonates), acetates, citrates, maleates, fumarates, lactates(and other carboxylates), etc.

[0137] Examples of salts of the carboxyl group include alkali metalsalts, such as lithium salts, sodium salts, potassium salts, etc.;alkaline earth metal salts, such as magnesium salts, calcium salts,etc.; ammonium salts, triethylamine salts, N-methylglucamine salts,tris-(hydroxymethyl)aminomethane salts; etc., and these could either beinorganic salts or organic salts.

[0138] Also, these free form, acid addition salts and salts of carboxylgroup of the quinolone carboxylic acid derivative may be present ashydrates.

[0139] Though in the case where a compound of this invention is used forantibacterial purposes, a carboxylic acid compound wherein thesubstituent R³ is a hydrogen atom is preferably used, a quinolonederivative whose carboxylic acid moiety is an ester is useful as asynthesis intermediate or a prodrug. For example, alkyl esters, benzylesters, alkoxyalkyl esters, phenylalkyl esters, and phenyl esters areuseful as synthesis intermediates.

[0140] Also, the ester to be used as a prodrug is an ester which iseasily hydrolyzed in the living body and form free form of carboxylicacid, and its examples include oxoalkyl esters, such as acetoxymethylester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester,dimethylaminoethyl ester, 5-indanyl ester, phthalidinyl ester,5-alkyl-2-oxo-1,3-dioxole-4-ylmethyl esters, and 3-acetoxy-2-oxobutylester.

[0141] Further, a quinolone derivative, wherein one of either of thesubstituents R⁵ and R⁶ is a hydrogen atom and the other is a substitutedcarboxyl group derived from an amino acid, a dipeptide, or a tripeptide,is useful as a prodrug.

[0142] An amino acid, a dipeptide, or a tripeptide to be used forobtaining such a prodrug is one wherein the peptide bond, which isformed by the carboxyl group derived from the amino acid, dipeptide, ortripeptide and the amino group that exists on the substituent at the7-position of the quinolone carboxylic acid derivative, can be easilyhydrolyzed in the living body and form free form of amine, and itsexamples include those derived from glycine, alanine, aspartic acid, andother amino acids, glycine-glycine, glycine-alanine, alanine-alanine,and other dipeptides, and glycine-glycine-alanine,glycine-alanine-alanine, and other tripeptides.

[0143] The compound of this invention represented by the formula (I) canbe produced by various methods, and in a preferred example, such acompound can be produced for example by reacting a compound representedby formula (III):

[0144] [wherein X² represents a substituent which functions as a leavinggroup, such as a substituted or unsubstituted phenylsulfonyl group, asubstituted or unsubstituted alkylsulfonyl group having 1 to 3 carbonatoms, a fluorine atom, a chlorine atom or a bromine atom;

[0145] R³¹ is the R³ defined in the formula (I) or a boron-containinggroup represented by formula (IV):

—B(Y³²)Y³³  (IV)

[0146]  (wherein Y³² and Y³³ may be the same or different from eachother with each being a fluorine atom or an alkylcarbonyloxy grouphaving 2 to 4 carbon atoms); and

[0147] R¹, R², R⁴, R⁵, R⁶, and A are as defined in the formula (I)] witha compound of the following formula (V) or an addtion salt thereof:

[0148]  [wherein each of R⁵¹ and R⁶¹ independently represents a hydrogenatom, an alkyl group having 1 to 6 carbon atoms or a protective groupfor an amino group, or one of either R⁵¹ or R⁶¹ represents a hydrogenatom and the other represents a substituted carboxyl group derived froman amino acid, a dipeptide, or a tripeptide with an amino group that isunsubstituted or is protected by a protective group for an amino group,and

[0149] this alkyl group may have a substituent selected from the groupconsisting of an alkylthio group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, a hydroxyl group, and a halogen atom,and

[0150] n is the same as defined in the formula (I)]

[0151] (in the case where an addition salt is used, the reaction iscarried out under the presence of reagents that cause the addition saltto become a free form).

[0152] Examples of the acid addition salts include inorganic acid salts,such as hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides,phosphates, etc.; and organic acid salts, such as methanesulfonates,benzenesulfonates, toluenesulfonates (and other sulfonates), acetates,citrates, maleates, fumarates, lactates (and other carboxylates); etc.

[0153] The reaction may be carried out using a solvent or without usinga solvent. A solvent to be used in the reaction may be any solvent whichhave no an adverse effect on the reaction, and its examples includedimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform,dimethylformamide, dimethylacetamide, N-methylpyrrolidone,tetrahydrofuran, water, 3-methoxybutanol, or a mixture of thereof.

[0154] The reaction is preferably carried out under the presence of anacid receptor, such as an inorganic base or an organic base, forexample, an inorganic basic compound, such as a carbonate or bicarbonateof an alkaline metal or an alkaline earth metal, or an organic basiccompound, such as triethylamine, pyridine, 1,8-diazobicycloundecene,N-methyl piperidene, N,N-diisopropylethylamine, etc.

[0155] The reaction temperature should normally be in the temperaturerange of room temperature to 200° C. and preferably in the range of 25to 150° C. The reaction time should be in the range of 30 minutes to 48hours, and the reaction is normally completed in approximately 30minutes to 8 hours.

[0156] The protective group of an amino group may be any protectivegroup that is generally used in the relevant field, and its examplesinclude alkoxycarbonyl groups, which may have a substituent, such astert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, etc.;aralkyloxycarbonyl groups, which may have a substituent, such asbenzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group,para-nitrobenzyloxycarbonyl group, etc.; acyl groups, which may have asubstituent, such as acetyl group, methoxyacetyl group, trifluoroacetylgroup, chloroacetyl group, pivaloyl group, formyl group, benzoyl group,etc.; alkyl groups, which may have a substituent, and aralkyl groups,which may have a substituent, such as tert-butyl group, benzyl group,para-nitrobenzyl group, para-methoxybenzyl group, triphenylmethyl group,etc.; ethers, which may have a substituent, such as methoxymethyl group,tert-butoxymethyl group, tetrahydropyranyl group,2,2,2-trichloroethoxymethyl group, etc.; and substituted silyl groups,such as trimethylsilyl group, isopropyldimethylsilyl group,tert-butyldimethylsilyl group, tribenzylsilyl group,tert-butyldiphenylsilyl group, etc.

[0157] In the case where each of R³ and R³¹ is an alkyl group havingfrom 1 to 6 carbon atoms, an alkoxymethyl group having from 2 to 7carbon atoms or a phenylalkyl group (aralkyl group) composed of analkylene group having 1 to 6 carbon atoms and a phenyl group, it can beconverted into a corresponding carboxylic acid by treatment under acidicor basic conditions which are generally used for the hydrolysis ofcarboxylic acid esters.

[0158] In the case where R³¹ has a structure of the formula (IV), it canbe converted into a corresponding carboxylic acid by subjecting it tohydrolysis under acidic or basic conditions after allowing the compound(V) to react with the compound (III).

[0159] In the case where deprotection is necessary, the compound ofinterest represented by the formula (I) can be obtained by removing theprotective group under appropriate conditions suitable for theprotective group.

[0160] A compound of the formula (V) may be produced by various methods,and though a method shown in PCT/JP96/00208 maybe given as an example,the method of production is not limited to thereto.

[0161] A compound of the formula (V) can be produced by removing Q froma compound represented by the following formula (VI):

[0162] [In the above formula (VI), R⁵¹² is the same as the R⁵ defined inthe formula (I) or represents a protective group of an amino group, R⁶and n are the same as defined in the formula (I), Q is a protectivegroup of an amino group,

[0163] wherein the protective group of an amino group may be selectedfrom the group consisting of a (substituted) alkoxycarbonyl group, a(substituted) aralkyloxycarbonyl group, a (substituted) acyl group, a(substituted) alkyl group, a (substituted) aralkyl group and asubstituted silyl group.]

[0164] An above-described compound may be present in the form of a saltthereof, a hydrate thereof, or a hydrate of the salt. Examples of theacid addition salt include inorganic acid salts and organic acid salts.Specific examples thereof include inorganic acid salts, such ashydrochlorides, sulfates, hydrobromides, hydroiodides, phosphates, etc.;and organic acid salts, such as methanesulfonates, benzenesulfonates,toluenesulfonates (sulfonic acid salts); acetates, citrates, maleates,fumarates, lactates (carboxylic acid salts); etc.

[0165] When both R⁵¹² and Q are protective groups of an amino group,they may be the same or different from each other. However, it is morefavorable for the production of compound (I) that each is cut off underdifferent reaction conditions.

[0166] Examples of R⁵¹² and Q, which are protective groups of aminogroups, include the following. That is, examples thereof include a(substituted) alkoxycarbonyl group, a (substituted) aralkyloxycarbonylgroup, a (substituted) acyl group, a (substituted) alkyl group, a(substituted) aralkyl group, and a (substituted) silyl group.

[0167] Specific examples thereof include (substituted) alkoxycarbonylgroups, such as tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonylgroup, etc.; (substituted) aralkyloxycarbonyl groups, such asbenzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group,para-nitrobenzyloxycarbonyl group, etc.; (substituted) acyl groups, suchas acetyl group, methoxyacetyl group, trifluoroacetyl group,chloroacetyl group, pivaloyl group, formyl group, benzoyl group, etc.;(substituted) alkyl groups or (substituted) aralkyl groups, such astert-butyl group, benzyl group, para-nitrobenzyl group,para-methoxybenzyl group, triphenylmethyl group, etc.; (substituted)ethers, such as methoxymethyl group, tert-butoxymethyl group,tetrahydropyranyl group, 2,2,2-trichloroethoxymethyl group, etc.; andsubstituted silyl groups, such as trimethylsilyl group,isopropyldimethylsilyl group, tert-butyldimethylsilyl group,tribenzylsilyl group, tert-butyldiphenylsilyl group, etc.

[0168] In producing the compound (I) using an above-mentioned compoundhaving Q as a protective group, it is necessary to carry out thereaction by removing the protective group Q. In this case, its reactionwith the compound (III) or (V) may be carried out by a so-called one-potreaction or the reaction may be carried out after once isolating thecompound (V) by removing the protective group.

[0169] As with a compound of the formula (V), a compound of the formula(VI) can be produced by various methods, and though a method describedin PCT/JP96/00208 may be given as an example, the production method isnot limited thereto.

[0170] Cis-2-fluorocyclopropylamine comprised of a single isomer, whichis desirable for the synthesis of a compound of the formula (I)comprised of a single isomer, may synthesized for example by the methoddescribed in JP-A-2-231475 (the term “JP-A” as used herein means anunexamined published Japanese patent appliction”). Synthesis of thecompound of formula (I) comprised of a single isomer using an opticallyactive cis-2-fluorocyclopropylamine derivative obtained in the mannerdescribed above as a raw material, may be carried out for example inaccordance with the method described for example in JP-A-2-231475.

[0171] Specific examples of compounds of this invention include thefollowing:

[0172]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid [shown in the following formula];

[0173]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0174]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0175]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0176]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0177]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0178]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0179]5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-fluoro-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0180]5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0181]5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0182]10-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylicacid [shown in the following formula];

[0183]7-[3-(R)-(1-aminocyclobutyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0184]7-[3-(R)-(1-aminocyclobutyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0185]7-[3-(R)-(1-aminocyclobutyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0186]7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0187]7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0188]7-[3-(R)-[1-(ethylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0189]5-amino-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0190]10-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylicacid [shown in the following formula];

[0191]1-(cyclopropyl)-8-methyl-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid [shown in the following formula];

[0192] Since the compound of this invention has potent antibacterialactions, it can be used as medicaments for use in human bodies, animals,and fishes or as preservatives of agricultural chemicals and food.

[0193] In the case where the compound of this invention is used as amedicament for human bodies, its dose is within the range of from 50 mgto 1 g, preferably from 100 mg to 500 mg, per day per adult.

[0194] In the case of use as a medical drug for an animal, its dosevaries depending on the purpose of its administration (treatment orprevention), kind and size of each animal to be treated, kind and degreeof each infected pathogenic bacterium, but is within the range ofgenerally from 1 mg to 200 mg, preferably from 5 mg to 100 mg, per 1 kgbody weight of each animal as a daily dose.

[0195] The daily dose is administered once a day or by dividing it intotwo to four doses per day. As occasion demands, the daily dose mayexceed the abovementioned amounts.

[0196] Since the compounds of this invention are active against a broadrange of microorganisms which cause various infectious diseases, it cantreat, prevent or alleviate diseases caused by such pathogens.

[0197] Examples of bacteria and bacterioid microorganisms on which thecompounds of this invention are effective include the genusStaphylococcus, Streptococcus pyogenes, hemolytic streptococcus,enterococcus, pneumococcus, the genus Peptostreptococcus, Neisseriagonorrhoeae, Escherichia coli, the genera Citrobacter, the genusShigella, Klebsiella pneumoniae, the genera Enterobacter, the genusSerratia, the genus Proteus, Pseudomonas aeruginosa, Haemophilusinfluenzae, the genus Acinetobacter, the genus Campylobacter, Chlamydiatrachomatis, and the like.

[0198] Examples of the diseases caused by the above pathogens includefolliculitis, furuncle, carbuncle, erysipelas, phlegmon, lymphangitis(lymphadenitis), panaritium, subcutaneous abscess, hidrosadenitis,aggregated acne, infectious atheroma, anal abscess, mastitis,superficial secondary infections of traumatic wounds, burn wounds,operative wounds, etc., pharyngolaryngitis, acute bronchitis,tonsillitis, chronic bronchitis, bronchiectasis, diffusepanbronchiolitis, secondary infections of chronic respiratory diseases,pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis,gonococcal urethritis, non-gonococcal urethritis, cholecystitis,cholangitis, bacillary dysentery, enteritis, inflammation of the uterineappendages, intrauterine infection, bartholinitis, blepharitis,hordeolum, dacryocystitis, tarsadenitis, corneal ulcer, otitis medea,sinusitis, periodontitis, pericoronitis, jaw inflammation, peritonitis,endocarditis, sepsis, meningitis, skin infection, etc.

[0199] Further, examples of acid-fast bacteria on which the compounds ofthis invention are effective include tubercle bacilli [Mycobacterium(abbreviated as “M.” hereinafter) tuberculosis, M. bovis, M. africanum],a typical acid-fast bacteria [M. kansasii, M. marinum, M. scrofulaceum,M. avium, M. intracellulare, M. xenopi, M. fortuitum, M. chelonae], etc.

[0200] The acid-fast bacteria infections that are caused by thesepathogens are largely classified according to the causing bacteria intothe three types of tuberculosis, a typical acid-fast bacteria infection,and leprosy. In addition to the lungs, tubercle bacilli infections maybe seen in the thoracic cavity, trachea/bronchus, lymph nodes, in agenerally disseminated manner, in the bones and joints, meninges/brain,digestive organs (intestines, liver), skin, mammary glands, eyes, middleear/throat, urinary tract, male genitals, female genitals, etc. Thelungs are the main affected parts of a typical acid-fast bacteriainfections (non-tubercle acid-fast bacteria infections), and otherexamples of a typical acid-fast bacteria infections include locallymphadenitis, soft skin tissue infections, articular infections,general dissemination type infections, etc.

[0201] The compounds of this invention are also effective againstvarious microorganisms that cause infections in animals. Examples ofsuch microorganisms include Escherichia, Salmonella, Pasturella,Haemophilus, Bordetella, Staphylococcus, Mycoplasma, etc.

[0202] Specific examples of fowl diseases include escherichiosis,pullorum disease, fowl paratyphoid fever, fowl cholera, infectiouscoryza, staphylococcal infection, Mycoplasma infection, etc., specificexamples of pig diseases include escherichiosis, salmonellosis,pasturellosis, Haemophilis infection, atrophic rhinitis, exudativeepidermitis, Mycoplasma infection, etc., specific examples of cattlediseases include escherichiosis, salmonellosis, hemorrhagic septicemia,Mycoplasma infection, contagious bovine pleuropneumonia, mastitis, etc.,specific examples of dog diseases include coliemia, Salmonellainfection, hemorrhagic septicemia, pyometra, cystitis, etc., andspecific examples of cat diseases include exudative pleurisy, cystitis,chronic rhinitis, Haemophilus infection, kitten diarrhea, Mycoplasmainfection, etc.

[0203] An antibacterial preparation which comprises the compound of thisinvention can be prepared by selecting an appropriate pharmaceuticalpreparation in accordance to the method of administration and using anyof the generally used methods of preparing various pharmaceuticalpreparations. With regard to the dosage forms of antibacterialpreparations having the compound of this invention as its principleagent, tablets, powders, granules, capsules, solutions, syrups, elixirs,oily or aqueous suspensions, etc. can be given as examples of forms oforal pharmaceutical preparations.

[0204] In the case of injections, a stabilizing agent, an antisepticagent, a solubilizing agent, etc. may be used in the preparation, or asolution which may contain these auxiliary agents may be contained in acontainer and thereafter made into a solid preparation by freeze-dryingor the like means to be re-dissloved when used. Also, a single dose maybe contained in a single container or multiple doses may be contained inthe same container.

[0205] Examples of forms of external-use preparations include solutions,suspensions, emulsions, ointments, gels, creams, lotions, sprays, etc.

[0206] A solid preparation may contain pharmaceutically acceptableadditives together with the active compound. For example, fillers,extenders, binders, disintegrators, solubilization enhancing agents,moistening agents, lubricating agents, etc. may be selected and mixed asnecessary to form a preparation.

[0207] Examples of forms of liquid preparations include solutions,suspensions, emulsions, and these may contain suspending agents,emulsifying agents, etc. as additives.

[0208] Examples of methods of administering the compound of thisinvention to an animal include a method of direct oral administration ororal administration by mixing it with feed, a method of preparing asolution and then performing oral administration of the solutiondirectly or upon addition of the solution to drinking water or feed, amethod of injection administration, etc.

[0209] A pharmaceutical preparation for administering the compound ofthis invention to an animal can be prepared optionally as powders, finegranules, soluble powders, syrups, solutions, or injections by thetechniques generally used in the relevant field.

[0210] Formulation examples of pharmaceutical preparations are shownbelow. Formulation Example 1 (Capsule): Compound of Example 1 100.0 mgCorn starch 23.0 mg CMC calcium 22.5 mg Hydroxymethyl cellulose 3.0 mgMagnesium stearate 1.5 mg Total 150.0 mg Formulation Example 2(Solution): Compound of Example 1 1 to 10 g Acetic acid or sodiumhydroxide 0.5 to 2 g Ethyl para-hydroxybenzoate 0.1 g Purified water88.9 to 98.4 g Total 100 g Formulation Example 3 (Powder to be mixed infeed) Compound of Example 1 1 to 10 g Corn starch 98.5 to 89.5 g Lightsilicic anhydride 0.5 g Total 100 g

BEST MODE OF CARRYING OUT THE INVENTION

[0211] The following describes the invention based on examples andreference examples, though this invention is not limited to thereto.

REFERENCE EXAMPLE 1

[0212] Ethyl 2-(2,4-difluoro-3-methylbenzoyl)-3-dimethylaminoacrylate

[0213] 2,4-Difluoro-3-methylbenzoate (4.97 g, 28.9 mmol) was dissolvedin toluene (50 ml), and after adding N,N-dimethylformamide (0.1 ml) andthionyl chloride (3.16 ml, 43.4 mmol) thereto, it was stirred for 14hours in an oil bath of 80° C. The reaction solution was then cooled andthereafter concentrated under a reduced pressure. After adding tolueneto the residue and repeating concentration under a reduced pressure, theresidue obtained was dissolved in tetrahydrofuran (10 ml). This solutionwas added dropwise while cooling with ice to a solution in which ethyl3-dimethylaminoacrylate (4.97 g, 34.7 mmol) and triethylamine (5.04 ml,36.1 mmol) were dissolved in tetrahydrofuran (20 ml). After completionof dripping, the reaction solution was heated under reflux for 10 hours.After completion of the reaction, the reaction solution was filtered,the triethylamine hydrochloride salt was removed (by diethyl etherwashing), and the filtrate was concentrated under a reduced pressure.The residue obtained was applied to a short silica gel chromatographyand 6.70 g (78%) of the title compound was obtained in the form of ayellow powder from an n-hexane:ethyl acetate=1:1 eluate.

[0214]¹H-NMR (400 MHz, CDCl₃) δ: 0.95 (3H, t, J=7.08 Hz), 2.18 (3H, t,J=1.95 Hz), 2.92-3.24 (6H, m), 3.99 (2H, q, J=7.08 Hz), 6.86 (1H, dt,J=1.22, 8.55 Hz), 7.43 (1H, brs), 7.75 (1H, s).

[0215] IR (KBr, disk): 3055, 2985, 2933, 2875, 2814, 1942, 1693, 1630,1593, 1477, 1431, 1379, 1277, 1255, 1221 cm⁻¹.

[0216] Melting point: 82 to 84° C.

[0217] Elemental analysis: As C₁₅H₁₇F₂NO₃; Calcd.: C, 60.60; H, 5.76; N,4.71 Found: C, 60.31; H, 5.73; N, 4.73

REFERENCE EXAMPLE 2

[0218] Ethyl7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylate

[0219] Ethyl 2-(2,4-difluoro-3-methylbenzoyl)-3-dimethylaminoacrylate(1.06 g, 3.57 mmol) was dissolved in tetrahydrofuran (15 ml), and afteradding the para-toluenesulfonic acid salt of (1R,2S)-2-fluorocyclopropylamine (970 mg, 3.93 mmol), a solution, in whichtriethylamine (552 μl, 3.96 mmol) was dissolved in tetrahydrofuran (5ml), was added dropwise under stirring at −15° C. After stirring thereaction solution for 2 hours at room temperature, potassium carbonate(740 mg, 5.36 mmol) and tetrabutylammonium chloride (49.6 mg, 0.179mmol) were added, and this reaction suspension was heated under refluxwhile stirring for 5 days. After cooling the reaction solution, thetetrahydrofuran was evapolated under a reduced pressure. Dichloromethane(10 ml) was then added to the residue, and while cooling with ice andstirring, 2 mol/l hydrochloric acid was added dropwise gradually toadjust the pH to approximately 3. Then after stirring for 15 minutes atroom temperature, extraction with dichloromethane (60 ml×3) wasperformed. After drying over anhydrous sodium sulfate, filtration wasperformed, the filtrate was concentrated under a reduced pressure, andthe crude crystals obtained were stirred and purified in the slurrystate in ethyl acetate. 713 mg (65%) of the title compound was therebyobtained in the form of colorless crystals.

[0220]¹H-NMR (400 MHz, CDCl₃) δ: 1.41 (3H, t, J=7.08 Hz), 1.56-1.62 (2H,m), 2.66 (3H, d, J=2.69 Hz), 3.85-3.89 (1H, m), 4.39 (2H, q, J=7.08 Hz),4.78-4.79 and 4.94-4.95 (1H, dm, J=62.74 Hz), 7.13 (1H, t, J=8.91 Hz),8.36 (1H, dd, J=6.71, 8.91 Hz), 8.56 (1H, d, J=2.93 Hz).

[0221] IR (KBr, disk): 3438, 3097, 2983, 2939, 2902, 1907, 1720, 1630,1593, 1566, 1460, 1429, 1387, 1367, 1311, 1250 cm⁻¹.

[0222] Melting point: 187 to 188° C.

[0223] Elemental analysis: As C₁₆H₁₅F₂NO₃; Calcd.: C, 62.54; H, 4.92; N,4.56 Found: C, 62.41; H, 4.87; N, 4.53

REFERENCE EXAMPLE 3

[0224]7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoguinoline-3-CarboxylicAcid

[0225] Ethyl7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate(1.40 g, 4.56 mmol) was dissolved in acetic acid (4 ml), and afteradding concentrated hydrochloric acid (4 ml) thereto, it was heatedunder reflux for 3 hours. After cooling, the reaction solution waspoured into ice water (50 ml) and the precipitated crystals werefiltered out. After washing the filtered-out crystals with an excessamount of water, washing in cold ethanol and washing in diethyl etherwere performed in that order, and after drying under a reduced pressure,1.18 g (93%) of the title compound was obtained in the form of a whitepowder.

[0226]¹H-NMR (400 MHz, CDCl₃) δ:1.48-1.72 (2H, m), 2.75 (3H, t, J=2.56Hz), 4.01 (1H, dd, J=2.81, 5.25 Hz), 4.83-4.84 and 4.98-5.00 (1H, dm,J=62.74 Hz), 7.31 (1H, dd, J=2.20, 8.79 Hz), 8.40-8.44 (1H, m), 8.84(1H, d, J=2.69 Hz), 14.50 (1H, brs).

[0227] IR (KBr, disk): 3097, 3014, 2956, 2642, 1957, 1728, 1618, 1566,1508, 1469, 1435, 1389, 1321, 1254, 1200 cm⁻¹.

[0228] Melting point: 250 to 253° C.

[0229] [α]_(D) ^(24.3)=−50.00° (c 0.145, 0.1 mol/l NaOH)

[0230] Elemental analysis: As C₁₄H₁₁F₂NO₃; Calcd.: C, 60.22; H, 3.97; N,5.02 Found: C, 59.92; H, 3.98; N, 4.92

EXAMPLE 1

[0231]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-CarboxylicAcid

[0232] After adding3-(R)-[1-tert-butoxycarbonylaminocyclopropyl]pyrrolidine (185 mg, 817μmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (2 ml),7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (190 mg, 681 μmol) was added thereto and it was heated under refluxfor 17 hours under a nitrogen atmosphere. After concentrating thereaction solution under a reduced pressure, the residue was dissolved inchloroform (50 ml). After washing the organic layer with a 10% aqueouscitric acid solution (25 ml), the organic layer was dried over anhydroussodium sulfate. After filtering, the filtrate was concentrated under areduced pressure, and after adding dropwise concentrated hydrochloricacid (5 ml) to the residue while cooling with ice, stirring at roomtemperature was performed for 30 minutes. 1 mol/l Hydrochloric acid (5ml) was then added to the reaction solution, and after washing theyellow acidic aqueous solution with chloroform (20 ml×3), the pH wasadjusted to 12.0 with an aqueous sodium hydroxide solution and theinsolubles were removed by filtration. After adjusting the pH of thebasic aqueous solution to 7.4 using 1 mol/l hydrochloric acid,extraction with chloroform (100 ml×4) was performed. After drying overanhydrous sodium sulfate, the solvent was evapolated under a reducedpressure. The residue thus obtained was purified by preparativechromatography (development at the lower layer of a 7:3:1 mixture ofchloroform:methanol:water), recrystallized in ethanol, and dried under areduced pressure. 112 mg (43%) of the title compound was therebyobtained in the form of yellow crystals.

[0233]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.54 (4H, d, J=5.61 Hz),1.19-1.21 (1H, m), 1.58-1.62 (1H, m), 1.66-1.69 (1H, m), 2.00-2.01 (1H,m), 2.16-2.17 (1H, m), 2.35 (3H, s), 3.16-3.23 (2H, m), 3.37-3.42 (1H,m), 3.54-3.55 (1H, m), 4.04-4.05 (1H, m), 4.94-4.95 and 5.10-5.11 (1H,dm, J=62.16 Hz), 7.01 (1H, d, J=8.78 Hz), 7.95 (1H, d, J=8.78 Hz), 8.43(1H, s).

[0234] IR (KBr, disk): 3375, 3062, 3006, 2925, 2864, 1728, 1610, 1508,1475, 1431, 1394, 1348, 1315, 1257 cm⁻¹.

[0235] Melting point: 228 to 230° C.

[0236] [α]_(D) ^(24.7)=−235.09° (c 0.285, 0.1 mol/l NaOH)

[0237] Elemental analysis: As C₂₁H₂₄FN₃O₃; Calcd.: C, 65.44; H, 6.28; N,10.90 Found: C, 65.10; H, 6.32; N, 10.76

REFERENCE EXAMPLE 4

[0238] Ethyl7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoguinoline-3-carboxylate

[0239] A mixture of ethyl (2,4-difluoro-3-methoxy)benzoyl acetate (48.8g, 189 mmol), synthesized by the method described in PCT/US98/19138,triethyl orthoformate (78.6 ml, 472 mmol) and acetic anhydride (250 ml)was stirred while heating for 6 hours in an oil bath of an externaltemperature of 120° C. After letting the reaction solution cool,concentration under a reduced pressure and solidification by drying wereperformed. The yellow extract obtained was then dissolved in toluene(800 ml), the para-toluenesulfonic acid salt of (1R,2S)-2-fluorocyclopropylamine (60.1 g, 246 mmol) was added, and whilestirring at −15° C., a solution, in which triethylamine (40.8 ml, 293mmol) was dissolved in toluene (200 ml), was added dropwise thereto.After stirring the reaction solution for 4 hours at room temperature,water (500 ml) was added, and the organic layer was separated. Afterwashing the organic layer with saturated saline solution (500 ml×2), itwas dried over anhydrous sodium sulfate. After filtering, the filtratewas concentrated under a reduced pressure and dried. The yellow oilysubstance obtained was then dissolved in 1,4-dioxane (600 ml), and whilecooling with water, 60% oily sodium hydride (5.94 g, 242 mmol) was addedgradually. After stirring the reaction mixture for 30 minutes at roomtemperature, concentration under a reduced pressure was performed untilthe volume of the reaction solution became approximately 300 ml. Theconcentrate thus obtained was slowly poured into 1 mol/l hydrochloricacid, which was stirred and cooled with water, and the precipitatedcrystals were filtered out. After washing these crystals with excesspurified water, a small amount of ethanol, and excess diethyl ether, inthat order, the crude crystals obtained where slurried in ethyl acetateand purified. 49.4 g (80.9%) of the title compound was thereby obtainedin the form of colorless crystals.

[0240]¹H-NMR (400 MHz, CDCl₃) δ: 1.42 (3H, t, J=7.08 Hz), 1.55-1.64 (2H,m), 3.88-3.93 (1H, m), 4.04 (3H, d, J=1.96 Hz), 4.39 (2H, q, J=7.08 Hz),4.78-4.79 and 4.94-4.95 (1H, dm, J=62.61 Hz), 7.22 (1H, t, J=8.79 Hz),8.24 (1H, dd, J=5.86, 8.79 Hz), 8.60 (1H, s).

[0241] Melting point: 190 to 193° C. (decomposed)

REFERENCE EXAMPLE 5

[0242]7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoguinoline-3-CarboxylicAcid

[0243] After dissolving ethyl7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (34.0 g, 105 mmol) in acetic acid (400 ml) and then addingconcentrated hydrochloric acid (400 ml) thereto, it was heated underreflux for 3 hours. After cooling, the reaction solution was poured intoice water (1500 ml), and the precipitated crystals were filtered out.After washing the filtered-out crystals with an excess amount of water,it was washed with cold ethanol and diethyl ether in that order, andafter drying under a reduced pressure, the crude crystals obtained werepurified by recrystallization from a mixed solvent ofacetonitrile-ethanol and then dried under a reduced presure. 27.1 g(87.4%) of the title compound was thereby obtained in the form of awhite powder.

[0244]¹H-NMR (400 MHz, CDCl₃) δ: 1.45-1.75 (2H, m), 3.87-3.95 (1H, m),4.03 (3H, d, J=1.95 Hz), 4.79-4.81 and 4.97-4.99 (1H, dm, J=62.68 Hz),7.30 (1H, t, J=8.79 Hz), 8.27 (1H, dd, J=5.86, 8.79 Hz), 8.76 (1H, s).

[0245] Melting point: 261-263° C. (decomposed)

EXAMPLE 2

[0246]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-CarboxylicAcid

[0247] After adding3-(R)-[1-tert-butoxycarbonylaminocyclopropyl]pyrrolidine (165 mg, 731μmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (2 ml),7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid (180 mg, 609 μmol) was added thereto and it was heated under refluxfor 13 hours under a nitrogen atmosphere. After concentrating thereaction solution under reduced pressure, the residue was dissolved inchloroform (100 ml). After washing the organic layer with a 10% aqueouscitric acid solution (50 ml), the organic layer was dried over anhydroussodium sulfate. After filtering, the filtrate was concentrated under areduced pressure, and after adding dropwise concentrated hydrochloricacid (5 ml) to the residue while cooling with ice, stirring wasperformed at room temperature for 30 minutes. 1 mol/l Hydrochloric acid(5 ml) was then added to the reaction solution, and after washing theyellow acidic aqueous solution with chloroform (50 ml×4), the pH wasadjusted to 12.0 with an aqueous sodium hydroxide solution and theinsolubles were removed by filtration. After adjusting the pH of thebasic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extractionwith chloroform (100 ml×4) was performed. After drying over anhydroussodium sulfate, the solvent was evapolated under a reduced pressure. Theresidue thus obtained was purified by preparative chromatography(development at the lower layer of a 7:3:1 mixture of chloroformmethanol:water), recrystallized in isopropyl alcohol, and dried under areduced pressure. 146 mg (60%) of the title compound was therebyobtained in the form of yellow crystals.

[0248]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.56 (4H, brs), 1.31-1.37 (1H,m), 1.50-1.56 (1H, m), 1.77-1.78 (1H, m), 2.02-2.04 (1H, m), 2.19-2.21(1H, m), 3.31-3.32 (1H, m), 3.49-3.51 (3H, m), 3.50 (3H, s), 4.00-4.02(1H, m), 4.93-4.94 and 5.09-5.10 (1H, dm, J=62.87 Hz), 7.01 (1H, s),7.90 (1H, d, J=9.03 Hz), 8.39 (1H, d, J=3.17 Hz)

[0249] IR (KBr, disk): 3373, 3315, 3091, 3003, 2976, 2935, 2856, 1903,1714, 1618, 1518, 1439, 1371, 1313, 1261, 1219 cm⁻¹.

[0250] Melting point: 189 to 192° C.

[0251] [α]_(D) ^(24.7)=−50.83° (c 0.240, 0.1 mol/l NaOH)

[0252] Elemental analysis: As C₂₁H₂₄FN₃O₃; Calcd.: C, 62.83; H, 6.03; N,10.47 Found: C, 62.50; H, 6.04; N, 10.26

EXAMPLE 3

[0253]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-cyclopropyl-1,4-dihydro-8-methyl-4-oxoguinoline-3-CarboxylicAcid

[0254] After adding3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (132 mg, 585μmol) and triethylamine (245 μl, 1.76 mmol) to dried dimethyl sulfoxide(1 ml),1-cyclopropyl-7-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid BF₂ chelate (181 mg, 585 μmol) was added thereto and it was stirredat room temperature for 87 hours under a nitrogen atmosphere. Afteradding cold water (50 ml) to the reaction solution and filtering out theprecipitated solids, the solids obtained were suspended in a mixedsolvent (200 ml) of ethanol/water (9:1), and triethylamine (1 ml) wasadded thereto and then heated under reflux for 7 hours. Afterconcentrating the reaction solution under a reduced pressure, theresidue was dissolved in chloroform (100 ml), and after washing theorganic layer with a 10% aqueous citric acid solution (50 ml), theorganic layer was dried over anhydrous sodium sulfate. After filtering,the filtrate was concentrated under a reduced pressure, and after addingdropwise the concentrated hydrochloric acid (2 ml) to the residue whilecooling with ice, it was stirred at room temperature for 30 minutes. 1mol/l Hydrochloric acid (2 ml) was then added to the reaction solution,and after washing the yellow acidic aqueous solution with chloroform (50ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxidesolution. After adjusting the pH of the basic aqueous solution to 7.4with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×4)was performed. After drying over anhydrous sodium sulfate, the solventwas evapolated under a reduced pressure. The residue thus obtained waspurified by recrystallization in ethanol and then dried under a reducedpressure. 99.6 mg (46%) of the title compound was thereby obtained inthe form of yellow crystals.

[0255]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.55-0.57 (4H, m), 0.74-0.76(1H, m), 0.90-0.92 (1H, m), 1.11-1.13 (1H, m), 1.24-1.26 (1H, m),1.75-1.77 (1H, m), 2.03-2.05 (1H, m), 2.21-2.24 (1H, m), 2.48 (3H, s),3.29-3.38 (3H, m), 3.53-3.55 (1H, m), 4.10-4.12 (1H, m), 7.07 (1H, s),7.96 (1H, s), 8.57 (1H, s).

[0256] Melting point: 230 to 233° C.

[0257] Specific rotation: [α]_(D) ^(24.7)=−169.35° (c 0.385, 0.1 mol/lNaOH)

[0258] Elemental analysis: As C₂₁H₂₅N₃O₃; Calcd.: C 68.48%; H 6.86%; N11.44% Found: C 68.46%; H 6.71%; N 11.38%

REFERENCE EXAMPLE 6 Ethyl 2-(2,6-dichloronicotinoyl)Acetate

[0259] Monoethyl malonate (6.61 g, 50.0 mmol) was dissolved in anhydroustetrahydrofuran (100 ml), and after adding magnesium ethoxide (3.15 g,28.0 mmol) thereto while cooling with ice, it was stirred at roomtemperature for 3 hours. The reaction solution was then concentratedunder a reduced pressure, thereby preparing a magnesium salt ofmonoethyl malonate. 2,6-dichloronicotinic acid (3.84 g, 20.0 mmol) wasthen dissolved in anhydrous tetrahydrofuran (80 ml), and after adding1,1-carbonyldiimidazole (4.87 g. 30.0 mmol) while cooling with ice, itwas stirred at room temperature for 1.5 hours. To this solution, asolution, wherein the previously prepared magnesium salt of monoethylmalonate was dissolved in anhydrous tetrahydrofuran (160 ml), was addeddropwise over a period of 10 minutes while cooling with ice. Aftercompletion of dripping, the temperature was gradually brought back toroom temperature and thereafter, stirring was performed for 4 hours.After adding ethyl acetate (200 ml) to the reaction solution, theorganic layer was washed with a 10% aqueous citric acid solution (150ml×2), saturated sodium bicarbonate water (150 ml), and saturated salinesolution (150 ml), in that order, and then dried over anhydrous sodiumsulfate. After filtering, the residue obtained by concentration under areduced pressure of the filtrate was applied to a silica gelchromatography, and 4.24 g (81%) of the title compound was obtained inthe form of a pale-pink, oily substance from an n-hexane:ethylacetate=3:1 eluate.

[0260]¹H-NMR (400 MHz, CHCl₃) δ: 1.12-1.40 (3H, m), 4.08 (1H, s),4.15-4.35 (2H, m), 5.72 (0.5H, s), 7.37 (1H, dd, J=14.5, 8.1 Hz), 9.49(1H, dd, J=16.4, 8.1 Hz), 12.52 (0.5H, s).

REFERENCE EXAMPLE 7

[0261] Ethyl2-(2,6-dichloronicotinoyl)-3-[2-(S)-fluoro-1-(R)-cyclopropylamino]Acrylate

[0262] Ethyl 2-(2,6-dichloronicotinoyl)acetate (7.03 g, 26.8 mmol) wasdissolved in acetic anhydride (30 ml), and after adding triethylorthoformate (60 ml) thereto, it was stirred in an oil bath of 140° C.for 2 hours. After letting the reaction solution cool, it wasconcentrated under a reduced pressure, and after adding toluene (50 ml)to the residue obtained, a concentration operation under a reducedpressure was performed. This operation was repeated 3 times, and theresidue obtained was dried under a reduced pressure. 8.42 g of ethyl2-(2,6-dichloronicotinoyl)-3-ethoxyacrylate was thereby obtained in theform of a yellow oily substance.

[0263] Next, this crude ethyl2-(2,6-dichloronicotinoyl)-3-ethoxyacrylate (2.11 g, 6.62 mmol) and thepara-toluenesulfonic acid salt of 2-(S)-fluoro-1-(R)-cyclopropylamine(2.45 g, 9.91 mmol) were suspended in dichloromethane (30 ml), andtriethylamine (2.77 ml, 19.87 mmol) was added dropwise gradually theretowhile stirring at −15° C. After completion of dripping, the reactionsolution was stirred at room temperature for 15 hours. After addingethyl acetate (100 ml) to the reaction solution, the organic layer waswashed with a 10% aqueous citric acid solution (80 ml), saturated sodiumbicarbonate water (80 ml), and saturated saline solution (80 ml), inthat order, and then dried over anhydrous sodium sulfate. Afterfiltering, the filtrate was concentrated under a reduced pressure, and20.10 g (90%, 2 processes) of the title compound was thereby obtained asa yellowish-brown, oily substance (E/Z mixture). This resultingsubstance was used in the subsequent reaction without furtherpurification.

[0264]¹H-NMR (400 MHz, CHCl₃) δ: 0.85-0.89 (0.7H, m), 1.00-1.04 (2.3H,m), 1.23-1.38 (2H, m), 3.01 (1H, m), 3.94-4.05 (2H, m), 4.65-4.84 (1H,m), 7.27-7.31 (1H, m), 7.50-7.57 (1H, m), 8.29-8.38 (1H, m), 11.02(0.8H, brd, J=12.5 Hz).

REFERENCE EXAMPLE 8

[0265] Ethyl7-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthylidine-3-carboxylate.

[0266] After dissolving ethyl2-(2,6-dichloronicotinoyl)-3-[2-(S)-fluoro-1-(R)-cyclopropylamino]acrylate(2.07 g, 5.97 mmol) in 1,4-dioxane (30 ml), 60% oily sodium hydride (287mg, 7.18 mmol) was added gradually thereto while stirring at 5° C. Thereaction suspension was then stirred for 1.5 hours at room temperatureand then concentrated under a reduced pressure. After dissolving theresidue in chloroform (100 ml), the organic layer was washed with a 10%aqueous citric acid solution (80 ml), saturated sodium bicarbonate water(80 ml), and saturated saline solution (80 ml), in that order, and thendried over anhydrous sodium sulfate. After filtering, the filtrate wasconcentrated under a reduced pressure, diethyl ether was added to theresidue thus obtained, and the precipitated crystals were filtered out,washed with diethyl ether, and then dried under a reduced pressure at60° C. for 16 hours. 1.25 g (67%) of the title compound was therebyobtained in the form of a white powder.

[0267]¹H-NMR (400 MHz, CHCl₃) δ: 1.41 (3H, t, J=7.1 Hz), 1.59-1.72 (2H,m), 3.58-3.63 (1H, m), 4.41 (2H, q, J=7.1 Hz), 4.93-5.12 (1H, m),7.39-7.41 (1H, m), 8.65-8.68 (2H, m).

[0268] MS (m/z): 310 (M+)

REFERENCE EXAMPLE 9:

[0269]7-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthylidine-3-CarboxylicAcid

[0270] A mixture of ethyl7-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthylidine-3-carboxylate(567 mg, 1.83 mmol), acetic acid (4 ml) and concentrated hydrochloricacid (2 ml) was heated under reflux for 2.5 hours. After cooling thereaction solution with ice, ice water (20 ml) was poured into thereaction solution, the precipitated crystals were filtered out, andafter washing with excess water, a small amount of cold ethanol, andexcess diethyl ether, the crystals were dried under a reduced pressureat 80° C. for 18 hours. 449 mg (87%) of the title compound was therebyobtained in the form of white needle crystals.

[0271]¹H-NMR (400 MHz, CHCl₃) δ: 1.70-1.80 (2H, m), 3.73-3.79 (1H, m),4.98-5.17 (1H, m), 7.56 (1H, d, J=8.3 Hz), 8.73 (1H, d, J=8.5 Hz), 8.97(1H, s), 14.11 (1H, brs).

[0272] Melting point: 215 to 220° C.

[0273] Specific rotation: [α]_(D) ^(24.5)=+26.90° (c 0.422, 0.1 mol/lNaOH)

[0274] Elemental analysis: As C₁₂H₈ClFN₂O₃; Calcd.: C 50.99%; H 2.85%; N9.91% Found: C 50.90%; H 2.71%; N 9.91%

[0275] MS (m/z): 282 (M⁺)

EXAMPLE 4

[0276]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthylidine-3-CarboxylicAcid

[0277] After adding3-(R)-[1-[N-(tert-butoxycarbonyl)amino]cyclopropyl]pyrrolidine (339 mg,1.50 mmol) and triethylamine (1.39 ml) to dried acetonitrile (10 ml),7-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthylidine-3-carboxylicacid (283 mg, 1.00 mmol) was added thereto and the mixture was heatedunder reflux for 1.5 hours under a nitrogen atmosphere. Afterconcentrating the reaction solution under a reduced pressure, theresidue was dissolved in a mixed solvent of ethyl acetate (100 ml) anddichloromethane (50 ml), and after washing the organic layer with a 10%aqueous citric acid solution (50 ml) and saturated saline solution (50ml) in that order, the organic layer was dried over anhydrous sodiumsulfate. After filtering, the filtrate was concentrated under a reducedpressure, and after adding dropwise concentrated hydrochloric acid (15ml) to the residue while cooling with ice, it was stirred at the sametemperature for 30 minutes. 1 mol/l Hydrochloric acid (10 ml) was thenadded to the reaction solution, and after washing the yellow acidicaqueous solution with chloroform (50 ml×4), the pH was adjusted to 11.0with an aqueous sodium hydroxide solution. After adjusting the pH of thebasic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extractionwith the lower layer (100 ml×2) of a 7:3:1 mixture ofchloroform:methanol:water was performed. The organic layers were thencombined, and after drying the organic layer over anhydrous sodiumsulfate, the solvent was evapolated under a reduced pressure. Theresidue obtained was purified by recrystallization in ethanol and thendried under a reduced pressure. 263 mg (74%) of the title compound wasthereby obtained in the form of white crystals.

[0278]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.49-0.55 (4H, m), 1.50-1.75(3H, m), 1.95-2.15 (2H, m), 3.00-3.80 (5H, m), 4.90-5.15 (1H, m), 6.38(1H, dm, J=9.1 Hz), 8.01 (1H, d, J=9.1 Hz), 8.31 (1H, s).

[0279] IR (KBr, disk) v: 3089, 3008, 2871, 1712, 1624, 1566, 1508, 1446,1379, 1333, 1257, 1187, 1136, 1095, 1024, 985 cm⁻¹.

[0280] Melting point: 216 to 218° C.

[0281] Specific rotation: [α]_(D) ^(24.5)=+63.50° (c 0.310, 0.1 mol/lNaOH)

[0282] Elemental analysis: As C₁₉H₂₁FN₄O₃; Calcd.: C 61.28%; H 5.68%; N15.04% Found: C 61.17%; H 5.66%; N 15.04%

[0283] MS (m/z): 373([M+H])⁺

REFERENCE EXAMPLE 10

[0284] Ethyl 2,4-difluorobenzoyl Acetate

[0285] Under a nitrogen atmosphere, monoethyl malonate (9.25 g, 70.0mmol) was dissolved in anhydrous tetrahydrofuran (150 ml), and afteradding magnesium ethoxide (4.17 g, 36.8 mmol) while cooling with ice, itwas stirred at room temperature for 1 hour. The reaction solution wasthen concentrated under a reduced pressure, thereby preparing amagnesium salt of monoethyl malonate. 2,4-difluorobenzoic acid (7.91 g,50.0 mmol) was then dissolved in anhydrous tetrahydrofuran (100 ml), andafter adding 1,1-carbonyldiimidazole (8.52 g. 52.5 mmol) while coolingwith ice, it was stirred at room temperature for 1 hour. To thissolution, a solution, wherein the previously prepared magnesium salt ofmonoethyl malonate was dissolved in anhydrous tetrahydrofuran (60 ml),was added dropwise while cooling with ice. After completion of dripping,the temperature was gradually brought back to room temperature andthereafter, stirring was performed for 16 hours. After adding toluene(100 ml) to the reaction solution, the organic layer was washed with a10% aqueous citric acid solution (200 ml), saturated sodium bicarbonatewater (150 ml), and saturated saline solution (150 ml), in that order,and then dried over anhydrous sodium sulfate. After filtering, theresidue obtained by concentration under a reduced pressure of thefiltrate was applied to a silica gel chromatography, and 11.0 g (95%) ofthe title compound was obtained in the form of a pale-yellow, oilysubstance from an n-hexane:ethyl acetate=9:1 eluate.

[0286]¹H-NMR (400 MHz, CHCl₃) δ: 1.24-1.36 (3H, m), 3.95 (2H×⅔, d,J=3.66 Hz), 4.20-4.30 (2H, m), 5.80 (1H×⅓, s), 6.86-7.02 (2H, m),7.88-8.04 (1H, m), 12.72 (1H×⅓, s).

Reference Example 11

[0287] Ethyl7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate

[0288] A mixture of ethyl 2,4-difluorobenzoyl acetate (5.50 g, 24.1mmol), triethyl orthoformate (8.00 ml, 48.2 mmol) and acetic anhydride(6.8 ml) was stirred in an oil bath of 120° C. for 16 hours. Afterletting the reaction solution cool, it was concentrated under a reducedpressure, and after adding toluene (30 ml) to the residue obtained, itwas concentrated under a reduced pressure again, and then dried under areduced pressure. A yellow oily substance was thereby obtained. Thissubstance was dissolved in toluene (100 ml), and after adding thepara-toluenesulfonic acid salt of 2-(S)-fluoro-1-(R)-cyclopropylamine(6.46 g, 26.1 mmol), triethylamine (4.95 ml, 35.6 mmol) was addeddropwise gradually thereto while stirring at −15° C. After completion ofdripping, the reaction solution was stirred at room temperature for 18hours. After adding water (150 ml) to the reaction solution, extractionwith ethyl acetate (150 ml×2) was performed. The organic layers werecombined and washed with saturated saline solution (150 ml) and thendried over anhydrous sodium sulfate. After filtering, the filtrate wasconcentrated under a reduced pressure, and a brown oily substance wasthereby obtained. After dissolving this substance in dimethylformamide(35 ml), potassium carbonate (6.55 g, 47.4 mmol) was added thereto andthen stirred at room temperature for 21 hour. Then while cooling withice and stirring, 2 mol/l hydrochloric acid (50 ml) was added graduallythereto and then stirred at room temperature for 6 hours. Theprecipitated crystals were filtered out and then washed with excesswater, a small amount of cold ethanol and excess diethyl ether. Thecrude crystals obtained were then purified by recrystallization in ethylacetate and then dried under a reduced pressure. 5.92 g (84%) of thetitle compound was thereby obtained.

[0289]¹H-NMR (400 MHz, CHCl₃) δ: 1.41-1.43 (3H, m), 1.69-1.76 (2H, m),3.39 (1H, brs), 4.37-4.43 (2H, m), 5.09 (1H, dm, J=62.46 Hz), 7.16-7.22(1H, m), 7.41-7.44 (1H, m), 8.49-8.57 (2H, m). Melting point: 227 to230° C.

Reference Example 12

[0290]7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-CarboxylicAcid

[0291] A mixture of ethyl7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate(4.08 g, 13.9 mmol), acetic acid (9 ml) and concentrated hydrochloricacid (9 ml) was heated under reflux for 21 hour. After cooling thereaction solution with ice, ice water (50 ml) was poured into thereaction solution, the precipitated crystals were filtered out, andafter washing with excess water, a small amount of cold ethanol andexcess diethyl ether, the crystals were dried under a reduced pressureat 80° C. for 16 hours. 3.51 g (95%) of the title compound was therebyobtained in the form of a white powder.

[0292]¹H-NMR (400 MHz, CDCl₃) δ: 1.78-1.84 (2H, m), 3.52-3.53 (1H, m),5.13 (1H, dm, J=64.59 Hz), 7.31-7.36 (1H, m), 7.59 (1H, d, J=9.26 Hz),8.54-8.53 (1H, m), 14.55 (1H, s).

[0293] Melting point: 302 to 305° C.

[0294] Specific rotation: [a]_(D) ²⁴³=+0.38° (c 0.560, 0.1 mol/l NaOH)

EXAMPLE 5

[0295]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoguinoline-3-CarboxylicAcid

[0296] After adding3-(R)-[1-[N-(tert-butoxycarbonyl)amino]cyclopropyl]pyrrolidine (203 mg,817 μmol) and triethylamine (0.5 ml) to dried dimethyl sulfoxide (1 ml),7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (197 mg, 743 μmol) was added thereto and the mixture was heatedreflux for 15 hours under a nitrogen atmosphere. After letting thereaction solution cool, water (30 ml) was added to the reaction solutionwhile cooling with ice, and the precipitated crystals were filtered outand washed well with water. After adding concentrated hydrochloric acid(5 ml) to the obtained crystals while cooling with ice, stirring at thesame temperature was performed for 30 minutes. 1 mol/l hydrochloric acid(10 ml) was then added to the reaction solution, and after washing theyellow acidic aqueous solution with chloroform (50 ml×2), the pH wasadjusted to 12.0 with an aqueous sodium hydroxide solution. Afteradjusting the pH of the basic aqueous solution to 7.4 with 1 mol/lhydrochloric acid, extractions into chloroform (100 ml×3) and a 95:5mixture of chloroform:methanol (100 ml×2) were performed. The organiclayers were then combined, and after drying the organic layer overanhydrous sodium sulfate, the solvent was evapolated under a reducedpressure. The residue obtained was purified by recrystallization inethanol and then dried under a reduced pressure. 203 mg (74%) of thetitle compound was thereby obtained in the form of yellow crystals.

[0297]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.50-0.54 (4H, m), 1.63-1.68(3H, m), 2.00-2.12 (2H, m), 2.94-2.97 (1H, m), 3.16-3.36 (4H, m), 5.16(1H, dm, J=62.40 Hz), 6.43 (1H, s), 6.67 (1H, d, J=9.02 Hz), 7.97 (1H,d, J=9.02 Hz), 8.32 (1H, s).

[0298] IR (KBr, disk) v: 3087, 3008, 2951, 2858, 1699, 1681, 1520, 1471,1458, 1396, 1363, 1371, 1250 cm⁻¹.

[0299] Melting point: 251 to 253° C.

[0300] Specific rotation: [α]_(D) ^(24.3)=+41.90° (c 0.160, 1 mol/lNaOH)

[0301] Elemental analysis: As C₂₀H₂₂FN₃O₃; Calcd.: C 64.68%; H 5.97%; N11.31% Found: C 64.69%; H 5.96%; N 11.25%

REFERENCE EXAMPLE 13

[0302]7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoguinoline-3-CarboxylicAcid BF₂ Chelate

[0303] While heating and stirring a mixed solution of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate(2.01 g, 5.00 mmol), acetic acid (5 ml) and acetic anhydride (5 ml) inan oil bath of 110° C., a boron trifluoride-tetrahydrofuran complex(0.83 ml, 7.50 mmol) was added dropwise over a period of 5 minutes.After stirring the reaction solution at the same temperature for 1.5hours, excess diethyl ether was added while cooling with ice, and theprecipitated solids were filtered out (and washed with diethyl ether).After drying under a reduced pressure at room temperature, 2.06 g (98%)of the title compound was obtained as a pale gray powder.

[0304]¹H-NMR (400 MHz, d₆-DMSO) δ: 1.15-1.30 (4H, m), 4.43 (1H, m), 7.20(1H, t, J=71.9 Hz), 8.25 (1H, d, J=8.8 Hz), 8.38 (1H, d, J=8.8 Hz), 9.36(1H, s).

EXAMPLE 6

[0305]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoguinoline-3-CarboxylicAcid

[0306] After adding3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (338 mg, 1.50mmol) and triethylamine (2091 μl, 1.50 mmol) to dried dimethyl sulfoxide(2 ml),7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid BF₂ chelate (422 mg, 1.00 mmol) was added thereto and stirred atroom temperature for 39 hours under a nitrogen atmosphere. Afterconcentrating the reaction solution under a reduced pressure, ethanol(20 ml), triethylamine (4 ml) and water (4 ml) were added to theconcentrate and heated under reflux for 3 hours. After concentrating thereaction solution under a reduced pressure, the residue was dissolved inchloroform (100 ml), and after washing the organic layer in a 10%aqueous citric acid solution (50 ml), the organic layer was dried overanhydrous sodium sulfate. After filtering, the filtrate was concentratedunder a reduced pressure, and after adding dropwise concentratedhydrochloric acid (5 ml) to the residue while cooling with ice, it wasstirred at room temperature for 30 minutes. 3 mol/l Hydrochloric acid(30 ml) was then added to the reaction solution, and after washing theyellow acidic aqueous solution with chloroform (50 ml×2), the pH wasadjusted to 11.0 with an aqueous sodium hydroxide solution. Afteradjusting the pH of the basic aqueous solution to 7.4 with 1 mol/lhydrochloric acid, extraction with chloroform (50 ml×2) was performed.After drying over anhydrous sodium sulfate, the solvent was evapolatedunder a reduced pressure. The residue thus obtained was purified byrecrystallization in a mixed solvent of ethanol/diethyl ether and thendried under a reduced pressure. 31 mg (8%) of the title compound wasthereby obtained in the form of a yellow powder.

[0307]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.57 (4H, brs), 0.81 (1H, m),1.03 (1H, m), 1.11 (1H, m), 1.25 (1H, m), 1.78 (1H, m), 2.05 (1H, m),2.22 (1H, m), 3.35-3.60 (4H, m), 4.08 (1H, m), 6.45 (1H, dd, J=76.3,73.8 Hz), 7.07 (1H, d, J=9.3 Hz), 8.00 (1H, d, J=9.3 Hz), 8.46 (1H, s).

[0308] Melting point: 206 to 207.5° C.

[0309] Specific rotation: [α]_(D) ^(24.5)=−67.70° (c 0.295, 0.1 mol/lNaOH)

[0310] Elemental analysis: As C₂₁H₂₃F₂N₃O₄.0.25CH₃CH₂OH; Calcd.: C59.92%; H 5.73%; N 9.75% Found: C 59.85%; H 5.62%; N 9.68%

REFERENCE EXAMPLE 14

[0311] Ethyl6-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-oxoguinoline-3-carboxylate

[0312] Ethyl6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate(10.04 g, 27.12 mmol) was dissolved in dimethylformamide (150 ml), and28% ammonia water (32.1 ml) was added dropwise thereto while stirringand cooling with ice. While sealing the reaction solution in a sealedtube, it was stirred at room temperature for 4 hours. The reactionsolution was then dissolved in methanol (200 ml) and concentrated undera reduced pressure. The residue obtained was purified byrecrystallization from a mixed solvent of 2-propanol/chloroform/28%ammonia water, and after drying under a reduced pressure, 7.07 g (71%)of the title compound was obtained as a yellow powder.

[0313]¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.44 (5H, m), 2.67 (3H, d, J=3.41Hz), 3.81-3.87 (1H, m), 4.33-4.41 (3H, m), 4.75-4.78 (0.5H, m),4.90-4.94 (0.5H, m), 8.47 (1H, d, J=3.41 Hz).

[0314] Elemental analysis: As C₁₆H₁₅F₂N₃O₅; Calcd.: C 52.32%; H 4.12%; N11.44% Found: C 52.62%; H 4.16%; N 11.12%

REFERENCE EXAMPLE 15

[0315] Ethyl7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate

[0316] Isoamyl nitrite (2.56 ml, 19.1 mmol) was added todimethylformamide (40 ml), and while stirring at 65° C., a solution,wherein ethyl6-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate(5.00 g, 13.6 mmol) was dissolved in dimethylformamide (60 ml), wasadded dropwise over a period of 3 hours. After completion of dripping,the reaction solution was stirred at 65° C. for 4 hours, allowed tocool, and then poured into water (500 ml). After extraction withchloroform (200 ml×3), the organic layers combined were washed with 1mol/l hydrochloric acid (200 ml) and saturated saline solution (100ml×2) in that order, and then dried over anhydrous sodium sulfate. Afterfiltering, the filtrate was concentrated under a reduced pressure, andthe residue obtained was applied to a silica gel chromatography toobtain 2.91 g (61%) of the title compound in the form of a white powderfrom a chloroform:methanol=30:1 eluate.

[0317]¹H-NMR (400 MHz, CDCl₃) δ: 1.37 (3H, t, J=7.08 Hz), 1.40-1.67 (2H,m), 2.70 (3H, d, J=2.93 Hz), 3.89-3.93 (1H, m), 4.34-4.40 (2H, m),4.79-4.83 (0.5H, m), 4.95-4.98 (0.5H, m), 8.55 (1H, d, J=2.93 Hz).

REFERENCE EXAMPLE 16

[0318] Ethyl5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate

[0319] Ethyl7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate(2.50 g, 7.10 mmol) was dissolved in acetonitrile (20 ml), and afteradding a 5% palladium carbon catalyst (water content: 50%, 1.0 g)thereto, it was stirred at room temperature for 20 hours under ahydrogen atmosphere at atmospheric pressure. After removing the catalystby filtering (methanol washing), the filtrate was concentrated under areduced pressure, and the residue obtained was dissolved in ethylacetate (10 ml) and heated under reflux for 30 minutes. n-hexane (10 ml)was then added, and after performing heated refluxing for 30 minutes,the reaction solution was allowed to stand under room temperature. Theprecipitated crystals were then filtered out, washed with a 1:1 mixedsolution of n-hexane:ethyl acetate and dried under a reduced pressure at60° C. for 16 hours. 869 mg (38%) of the title compound was therebyobtained as a yellow powder.

[0320]¹H-NMR (400 MHz, CDCl₃) 6:1.23-1.36 (1H, m), 1.38 (3H, t, J=7.08Hz), 1.43-1.56 (1H, m), 2.39 (3H, d, J=2.20 Hz), 3.70-3.77 (1H, m), 4.37(2H, q, J=7.08 Hz), 4.71-4.75 (0.5H, m), 4.87-4.90 (0.5H, m), 6.20 (1H,d, J=11.96 Hz), 8.37 (1H, d, J=3.42 Hz).

REFERENCE EXAMPLE 17

[0321]5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-CarboxylicAcid

[0322] Ethyl5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate (735 mg, 2.28 mmol) was dissolved in a 1:1 mixed solution (8 ml) ofacetic acid:water, and after adding concentrated sulfuric acid (90 μl)thereto, it was stirred for 4 hours in an oil bath of 120° C. Aftercooling the reaction solution with ice, water (20 ml) was pouredtherein, and the mixed reaction solution was stirred at room temperaturefor 2 hours. The precipitated crystals were filtered out, washed withexcess water, a small amount of cold ethanol and excess diethyl ether inthat order, and then dried under a reduced pressure at 80° C. for 17hours. 552 mg (82%) of the title compound was thereby obtained in theform of yellow crystals.

[0323]¹H-NMR (400 MHz, DMSO-d₆) δ: 1.23-1.38 (1H, m), 1.56-1.66 (1H, m),2.39 (3H, d, J=2.20 Hz), 4.14-4.22 (1H, m), 4.96-5.00 (0.5H, m),5.12-5.16 (0.5H, m), 6.50 (1H, d, J=12.70 Hz), 8.60 (1H, d, J=3.17 Hz).

[0324] Specific rotation: [α]_(D) ^(24.3)=−111.00° (c 0.510, 0.1 mol/lNaOH)

EXAMPLE 7

[0325]5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoguinoline-3-CarboxylicAcid

[0326] After adding3-(R)-[1-[N-(tert-butoxycarbonyl)amino]cyclopropyl]pyrrolidine (643 mg,2.55 mmol) and triethylamine (0.5 ml) to dried dimethyl sulfoxide (1ml),5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (250 mg, 850 μmol) was added thereto and stirred at 70° C. for 37hours while sealing under a nitrogen atmosphere. After letting thereaction solution cool, the reaction solution was concentrated under areduced pressure, the residue obtained was dissolved in ethyl acetate(100 ml), and washed with a 10% aqueous citric acid solution (50 ml) andsaturated saline solution (30 ml). The organic layer was then dried overanhydrous sodium sulfate, and after filtering, the filtrate wasconcentrated under a reduced pressure. The residue obtained was thenapplied to a short silica gel chromatography and crude crystals wereobtained from a chloroform:methanol=30:1 eluate. After adding dropwiseconcentrated hydrochloric acid (5 ml) to the crude crystals whilecooling with ice, it was stirred at the same temperature for 30 minutes.1 mol/l Hydrochloric acid (10 ml) was then added to the reactionsolution, and after washing the yellow acidic aqueous solution withchloroform (50 ml×2), the pH was adjusted to 12.0 with an aqueous sodiumhydroxide solution. After adjusting the pH of the basic aqueous solutionto 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100ml×3) was performed. The organic layers were then combined and driedover anhydrous sodium sulfate, and then the solvent was evapolated undera reduced pressure. The residue thus obtained was purified byrecrystallization from ethanol and then dried under a reduced pressure.32 mg (9%) of the title compound was thereby obtained in the form ofyellow crystals.

[0327]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.54-0.57 (1H, m), 0.60-0.67(1H, m), 1.23-1.55 (3H, m), 1.74-1.85 (1H, m), 1.97-2.17 (2H, m), 2.33(3H, s), 3.18-3.27 (2H, m), 3.43-3.47 (1H, m), 3.54-3.63 (1H, m),3.71-3.78(1H, m), 4.77-4.79(0.5H, m), 4.93-4.96(0.5H, m), 6.00 (1H, s),8.56 (1H, d, J=3.66 Hz).

[0328] IR (KBr, disk) v: 3402, 3344, 3276, 3097, 2918, 2864, 1724, 1616,1548, 1506, 1477, 1441, 1408 cm⁻¹.

[0329] Melting point: 240 to 242° C. (decomposed)

[0330] Specific rotation: [α]_(D) ^(23.5)=−225.91° (c 0.525, 0.1 mol/lNaOH)

[0331] Elemental analysis: As C₂₁H₂₅FN₄O₃; Calcd.: C 62.99%; H 6.29%; N13.99% Found: C 62.86%; H 6.38%; N 13.76%

REFERENCE EXAMPLE 18

[0332] Ethyl6-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-5-nitro-4-oxoguinoline-3-carboxylate

[0333] Ethyl6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate(13.96 g, 36.14 mmol) was dissolved in dimethylformamide (180 ml), and28% ammonia water (60 ml) was added dropwise in while stirring andcooling with ice. After stirring the reaction solution at roomtemperature for 64 hours, water (100 ml) was added to the reactionsolution and then concentrated under a reduced pressure. Thewater-containing residue obtained was then subjected to extraction withethyl acetate (100 ml×3), and the organic layers were then combined,washed with water (150 ml×3) and saturated saline solution (200 ml) inthat order, and then dried over anhydrous sodium sulfate. Afterfiltering, the filtrate was concentrated under a reduced pressure, theresidue obtained was applied to a silica gel chromatography, and 8.92 g(64%) of the title compound was obtained in the form of a pale red, oilysubstance from a chloroform:methanol=30:1 eluate.

[0334]¹H-NMR (400 MHz, CDCl₃) δ: 1.37 (3H, t, J=7.0 Hz), 1.49 (1H, ddd,J=9.5, 6.0, 3.5 Hz), 1.53-1.58 (1H, m), 3.68 (1H, dt, J=8.5, 5.5 Hz),4.11 (3H, d, J=2.5 Hz), 4.36 (2H, dq, J=7.0, 1.5 Hz), 4.51 (2H, br),4.83 (1H, ddt, J=63.3, 5.5, 3.5 Hz), 8.47 (1H, s).

[0335] IR (KBr, disk) v: 3379, 1724, 1608, 1525, 1471, 1323, 1259, 1063cm⁻¹.

[0336] HRMS (FAB): As C₁₆H₁₆F₂N₃O₆ (M⁺+1); Calcd.: 384.1007 Found:384.0974

REFERENCE EXAMPLE 19

[0337] Ethyl7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-5-nitro-4-oxoguinoline-3-carboxylate

[0338] Isoamyl nitrite (3.81 g, 32.5 mmol) was added todimethylformamide (60 ml), and while stirring at 7⁰° C., a solution,wherein ethyl6-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate(8.90 g, 23.2 mmol) was dissolved in dimethylformamide (120 ml), wasadded dropwise thereto over a period of 3 hours. After completion ofdripping, the reaction solution was stirred at 70° C. for 1 hour,allowed to cool, and then poured into water (500 ml). After extractionwith ethyl acetate (300 ml×3), the organic layers combined were washedwith 1 mol/l hydrochloric acid (300 ml) and saturated saline solution(200 ml×2) in that order, and then dried over anhydrous sodium sulfate.After filtering, the filtrate was concentrated under a reduced pressure,and the crude crystals obtained were recrystallized in ethanol and thendried under a reduced pressure. 3.81 g (45%) of the title compound wasthereby obtained in the form of yellow crystals.

[0339]¹H-NMR (400 MHz, CDCl₃) δ: 1.37 (3H, t, J=7.0 Hz), 1.55 (1H, ddd,J=9.5, 6.0, 3.5 Hz), 1.59-1.69 (1H, m) 3.93 (1H, dt, J=8.5, 5.5 Hz),4.11 (3H, t, J=2.5 Hz), 4.37 (2H, dq, J=7.0, 1.5 Hz), 4.86 (1H, dddd,J=63.0, 6.0, 5.5, 3.5 Hz), 7.20 (1H, d, J=10.0 Hz), 8.55 (1H, d, J=1.5Hz).

[0340] IR (KBr, disk) v: 3062, 1722, 1639, 1602, 1544, 1425, 1328, 1259,1057 cm⁻¹.

[0341] Melting point: 167 to 170° C. (decomposed)

[0342] Elemental analysis: As C₁₆H₁₄F₂N₂O₆; Calcd.: C 52.18%; H 3.89%; N7.61% Found: C 51.97%; H 3.78%; N 7.56%

REFERENCE EXAMPLE 20

[0343] Ethyl5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoguinoline-3-carboxylate

[0344] Ethyl7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate(3.71 g, 10.1 mmol) was dissolved in acetonitrile (50 ml), and afteradding a 5% palladium carbon catalyst (water content: 50%, 1.5 g)thereto, it was stirred at room temperature for 20 hours under ahydrogen atmosphere at atmospheric pressure. After removing the catalystby filtering (methanol washing), the filtrate was concentrated under areduced pressure, the residue obtained was applied to a silica gelchromatography, and 2.68 g (79%) of the title compound was obtained as ayellow amorphous substance from a chloroform:methanol=30:1 eluate.

[0345]¹H-NMR (400 MHz, CDCl₃) δ: 1.38 (3H, t, J=7.0 Hz), 1.43-1.57 (2H,m), 3.75-3.82 (4H, m), 4.37 (2H, q, J=7.0 Hz), 4.81 (1H, ddt, J=62.5,6.5, 3.5 Hz), 6.24 (1H, d, J=13.0 Hz), 8.37 (1H, d, J=2.0 Hz).

[0346] HRMS (FAB): As C₁₆H₁₇F₂N₂O₄ (M⁺+1); Calcd.: 339.1156 Found:339.1150

REFERENCE EXAMPLE 21

[0347]5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-CarboxylicAcid

[0348] A mixture of ethyl5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate(2.68 g, 7.92 mmol), acetic acid (20 ml) and concentrated hydrochloricacid (20 ml) was heated under reflux for 3 hours. After cooling thereaction solution with ice, water (200 ml) was poured therein and theprecipitated crystals were filtered out. After washing with excesswater, a small amount of cold ethanol and excess diethyl ether in thatorder, the crude crystals obtained were purified by recrystallization ina mixed solvent of chloroform/methanol and then dried under a reducedpressure. 1.26 g (51%) of the title compound was thereby obtained in theform of yellow crystals.

[0349]¹H-NMR (400 MHz, DMSO-d₆) δ: 1.54-1.64 (2H, m), 3.76 (3H, s),4.02-4.07 (1H, m), 4.89-5.10 (1H, m), 6.59 (1H, d, J=14.0 Hz), 7.73 (2H,br), 8.57 (1H, d, J=1.5 Hz).

[0350] IR (KBr, disk) v: 3432, 3328, 1699, 1576, 1518, 1281, 1236 cm⁻¹.

[0351] Melting point: 291 to 298° C. (decomposed)

[0352] Specific rotation: [α]_(D) ^(25.0)=+40.01° (c 0.305, 0.1 mol/lNaOH)

[0353] Elemental analysis: As C₁₄H₁₂F₂N₂O₄; Calcd.: C 54.20%; H 3.90%; N9.03% Found: C 54.10%; H 3.86%; N 9.02%

EXAMPLE 8

[0354]5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoguinoline-3-CarboxylicAcid

[0355] After adding3-(R)-[1-[N-(tert-butoxycarbonyl)amino]cyclopropyl]pyrrolidine (788 mg,3.48 mmol) and triethylamine (2 ml) to dried dimethyl sulfoxide (1 ml),5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid (621 mg, 2.00 mol) was added thereto and stirred at 90° C. for 168hours while sealing in a sealed tube under a nitrogen atmosphere. Afterletting the reaction solution cool and then concentrating the reactionsolution under a reduced pressure, the residue obtained was dissolved inchloroform (200 ml) and washed with a 10% aqueous citric acid solution(100 ml). The organic layer was then dried over anhydrous sodiumsulfate, and after filtering, the filtrate was concentrated under areduced pressure. After adding dropwise concentrated hydrochloric acid(10 ml) to the obtained residue while cooling with ice, it was stirredat the same temperature for 30 minutes. 1 mol/l Hydrochloric acid (20ml) was then added to the reaction solution, and after washing theyellow acidic aqueous solution with chloroform (50 ml×3), the pH wasadjusted to 12.0 with an aqueous sodium hydroxide solution. Afteradjusting the pH of the basic aqueous solution to 7.8 with 1 mol/lhydrochloric acid, extraction with chloroform (100 ml×3) was performed.The organic layers were then combined and dried over anhydrous sodiumsulfate, and then the solvent was evapolated under a reduced pressure.The residue thus obtained was purified by recrystallization from a mixedsolvent of ethanol and diethyl ether, and then dried under a reducedpressure. 74 mg (9%) of the title compound was thereby obtained in theform of yellow crystals.

[0356]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.48-0.53 (4H, m), 1.09-1.21(1H, m), 1.32-1.43 (1H, m), 1.64-1.75 (1H, m), 1.93-2.01 (1H, m),2.10-2.23 (1H, m), 3.21-3.23 (1H, m), 3.21-2.27 (1H, m), 3.36-3.43 (6H,m), 3.79-3.84 (1H, m), 4.85-4.84 (1H, m), 4.85-5.04 (1H, m), 6.06 (1H,s), 8.01 (1H, d, J=3.5 Hz).

[0357] IR (KBr, disk) v: 3454, 3410, 1716, 1617, 1577, 1548, 1511, 1232,1016 cm⁻¹.

[0358] Melting point: 172 to 178° C. (decomposed)

[0359] Elemental analysis: As C₂₁H₂₅FN₄O₄.0.75H₂O; Calcd.: C 58.66%; H6.21%; N 13.03% Found: C 58.58%; H 6.02%; N 12.76%

REFERENCE EXAMPLE 22

[0360] Ethyl 3-dimethylamino-2-(2,3,4-trifluorobenzoyl)Acrylate

[0361] A mixed solution of 2,3,4-trifluorobenzoic acid (10.3 g, 58.5mmol), thionyl chloride (6.4 ml, 87.8 mmol) and a catalytic amount ofdimethylformamide was heated under reflux for 30 minutes. After lettingthe reaction solution cool, the reaction solution was concentrated undera reduced pressure, toluene (30 ml) was added to the residue, andconcentration under a reduced pressure was performed again. The residueobtained was then dissolved in tetrahydrofuran (20 ml), and theresulting solution was added to a tetrahydrofuran (40 ml) solution ofethyl β-dimethylaminoacrylate (9.20 g, 64.3 mmol) and triethylamine(10.2 ml, 73.1 mmol) while stirring and cooling with ice. The reactionmixture was then stirred at room temperature for 1.5 hours and thenheated under reflux for 16.5 hours. After letting the reaction solutioncool, the precipitated solids were removed by filtration and thefiltrate was concentrated under a reduced pressure. The residue was thenapplied to a silica gel chromatography, and 15.1 g (86%) of the titlecompound was obtained from an n-hexane:ethyl acetate=3:1 eluate.

[0362]¹H-NMR (400 MHz, CDCl₃) δ: 1.00 (3H, t, J=7.1 Hz), 2.88 (3H, brs),3.33 (3H, brs), 4.01 (2H, q, J=7.1 Hz), 6.95-7.01 (1H, m), 7.34 (1H,brs), 7.80 (1H, s).

REFERENCE EXAMPLE 23

[0363] Ethyl10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-Carboxylate

[0364] Ethyl 3-dimethylamino-2-(2,3,4-trifluorobenzoyl)acrylate (15.0 g,49.8 mmol) was dissolved in ethanol (30 ml), and to this solution, anethanol (10 ml) solution of (S)-2-amino-1-propanol (4.50 g, 59.8 mmol)was added dropwise while stirring and cooling with ice. After completionof dripping, the reaction solution was stirred for 1 hour at roomtemperature and then concentrated under a reduced pressure. The residueobtained was dissolved in dimethyl sulfoxide (50 ml), and after addingspray-dried calcium fluoride (16 g) thereto, it was stirred at 120° C.for 26 hours. After letting the reaction suspension cool, the reactionsuspension was concentrated under a reduced pressure, chloroform (200ml) and water (200 ml) were added to the residue, and after performing aseparation operation, the water layer was extracted using chloroform(200 ml). The combined organic layers were then washed with saturatedsaline solution (100 ml) and then dried over anhydrous sodium sulfate.After filtering, the filtrate was concentrated under a reduced pressure,the residue obtained was applied to a silica gel chromatography, and5.60 g (39%) of the title compound was obtained as a white powder from achloroform:methanol=50:1 eluate.

[0365]¹H-NMR (400 MHz, CDCl₃) δ: 1.41 (3H, t, J=7.1 Hz), 1.61 (3H, d,J=7.1 Hz), 4.33-4.44 (5H, m), 7.18 (1H, t, J=10.0 Hz), 8.06 (1H, dd,J=10.0, 5.4 Hz), 8.39 (1H, s).

REFERENCE EXAMPLE 24

[0366]10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-CarboxylicAcid

[0367] A mixture of ethyl10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate(5.60 g, 19.2 mmol), acetic acid (25 ml) and concentrated hydrochloricacid (25 ml) was heated under reflux for 4 hours. After cooling thereaction solution with ice, water (100 ml) was added thereto, and theprecipitated crystals were filtered out and then washed with excesswater, a small amount of cold ethanol and excess diethyl ether in thatorder. The crude crystals obtained were then suspended in ethanol (40ml) and stirred under room temperature. The crystals were filtered out,washed with ethanol, and then dried under a reduced pressure at 80° C.for 17 hours. 4.10 g (81%) of the title compound was thereby obtained inthe form of a white powder.

[0368]¹H-NMR (400 MHz, DMSO-d₆) δ: 1.47 (3H, d, J=6.8 Hz), 4.44 (1H, d,J=9.6 Hz), 4.62 (1H, d, J=9.6 Hz), 4.99 (1H, q-like, J=6.8 Hz), 7.59(1H, t, J=9.1 Hz), 7.95 (1H, dd, J=9.1, 5.4 Hz, 9.07 (1H, s).

[0369] Elemental analysis: As C₁₃H₁₀FNO₄; Calcd.: C 59.32%; H 3.83%; N7.22% Found: C 59.60%; H 3.95%; N 6.99%

EXAMPLE 9

[0370]10-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-CarboxylicAcid

[0371] After adding3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (252 mg, 1.12mmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (3 ml),10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylicacid (244 mg, 928 μmol) was added thereto and stirred while heating inan oil bath of 100° C. for 18 hours under a nitrogen atmosphere. Afterconcentrating the reaction solution under a reduce pressure, the residuewas dissolved in chloroform (100 ml). After washing the organic layerwith a 10% aqueous citric acid solution (50 ml) and saturated salinesolution (50 ml), the organic layer was dried over anhydrous sodiumsulfate. After filtering, the filtrate was concentrated under a reducedpressure, and after adding dropwise concentrated hydrochloric acid (6ml) to the residue while cooling with ice, it was stirred at roomtemperature for 30 minutes. After adding 4 ml of water to the reactionsolution and washing this acidic aqueous solution with chloroform (10ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxidesolution. After adjusting the pH of the basic aqueous solution to 7.4with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3)was performed. After drying over anhydrous sodium sulfate, the solventwas evapolated under a reduced pressure. The residue thus obtained waspurified by recrystallization from ethanol and then dried under areduced pressure. 125 mg (36.5%) of the title compound was therebyobtained in the form of yellow crystals.

[0372]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.57 (4H, s), 1.54 (3H, d,J=6.80 Hz), 1.66-1.78 (1H, m), 2.01-2.11 (1H, m), 2.19-2.30 (1H, m),3.38-3.60 (4H, m), 4.25 (1H, d, J=11.0 Hz), 4.47 (1H, d, J=11.0 Hz),4.55-4.63 (1H, m), 7.11 (1H, d, J=9.03 Hz), 7.81 (1H, d, J=9.03 Hz),8.32 (1H, s).

[0373] IR (KBr, disk) v: 1634, 1529, 1446, 1429, 1363, 1269, 1227, 798cm⁻¹.

[0374] Melting point: 249 to 252° C. (decomposed)

[0375] Elemental analysis: As C₂₀H₂₃N₃O₄, HCl.O.5H₂O; Calcd.: C 57.90%;H 6.07%; N 10.13% Found: C 57.65%; H 5.87%; N 9.97%

EXAMPLE 10

[0376]1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1,4-dihydro-4-oxoquinoline-3-CarboxylicAcid

[0377] After adding3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine(118 mg, 436 μmol) and triethylamine (0.50 ml) to dried dimethylsulfoxide (1 ml),7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (122 mg, 436 μmol) was added thereto and heated under reflux in anoil bath of 100° C. for 18 hours under a nitrogen atmosphere. Afterconcentrating the reaction solution under a reduced pressure, theresidue was dissolved in chloroform (100 ml). After washing the organiclayer with a 10% aqueous citric acid solution (100 ml), the organiclayer was dried over anhydrous sodium sulfate. After filtering, thefiltrate was concentrated under a reduced pressure, and after addingdropwise concentrated hydrochloric acid (2 ml) to the residue whilecooling with ice, it was stirred at room temperature for 30 minutes.After adding 1 mol/l hydrochloric acid (2 ml) to the reaction solutionand washing the yellow acidic aqueous solution with chloroform (50ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxidesolution. After adjusting the pH of the basic aqueous solution to 7.4with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3)was performed. After drying over anhydrous sodium sulfate, the solventwas evapolated under a reduced pressure. The residue thus obtained wasthen purified by a preparative chromatography (developed into the lowerlayer of a 7:3:1 mixture of chloroform:methanol:water), purified furtherby recrystallization from ethanol, and then dried under a reducedpressure. 72.8 mg (42%) of the title compound was thereby obtained inthe form of yellow crystals.

[0378]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.59-0.64 (4H, m), 1.21-1.27(1H, m), 1.50-1.64 (2H, m), 1.99-2.01 (1H, m), 2.34 (3H, s), 2.42 (3H,s), 2.87-2.89 (1H, m), 3.27-3.29 (3H, m), 3.63-3.65 (1H, m), 4.06-4.07(1H, m), 5.05 (1H, dm, J=63.72 Hz), 7.09 (1H, m), 8.00 (1H, s), 8.44(1H, s).

[0379] IR (KBr, disk) v: 3348, 3086, 2939, 2844, 2789, 1711, 1614, 1518,1435, 1354, 1315, 1257, 1221 cm⁻¹.

[0380] Melting point: 223 to 224° C.

[0381] Specific rotation: [α]_(D) ^(24.7)=−119.66° (c 0.295, 0.1 mol/lNaOH)

[0382] Elemental analysis: As C₂₂H₂₆FN₃O₃; Calcd.: C 66.15%; H 6.56%; N10.52% Found: C 65.92%; H 6.52%; N 10.40%

EXAMPLE 11

[0383]1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1,4-dihydro-4-oxoguinoline-3-CarboxylicAcid

[0384] After adding3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine(102 mg, 379 μmol) and triethylamine (0.50 ml) to dried dimethylsulfoxide (1 ml),7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid (112 mg, 379 μmol) was added thereto and stirred while heating inan oil bath of 100° C. for 15 hours under a nitrogen atmosphere. Afterconcentrating the reaction solution under a reduced pressure, theresidue was dissolved in chloroform (100 ml). After washing the organiclayer with a 10% aqueous citric acid solution (100 ml), the organiclayer was dried over anhydrous sodium sulfate. After filtering, thefiltrate was concentrated under a reduced pressure, and after addingdropwise concentrated hydrochloric acid (2 ml) to the residue whilecooling with ice, it was stirred at room temperature for 30 minutes.After adding 1 mol/l hydrochloric acid (2 ml) to the reaction solutionand washing the yellow acidic aqueous solution with chloroform (50ml×4), the pH was adjusted to 12.0 with an aqueous sodium hydroxidesolution. After adjusting the pH of the basic aqueous solution to 7.4with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3)was performed. After drying over anhydrous sodium sulfate, the solventwas evapolated under a reduced pressure. The residue thus obtained wasthen purified by a preparative chromatography (developed into the lowerlayer of a 7:3:1 mixture of chloroform:methanol:water), purified furtherby recrystallization from ethanol, and then dried under a reducedpressure. 78.3 mg (50%) of the title compound was thereby obtained inthe form of yellow crystals.

[0385]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.57-0.61 (4H, m), 1.33-1.40(1H, m), 1.56-1.58 (2H, m), 1.99-2.01 (1H, m), 2.34 (3H, s), 2.87-2.89(1H, m), 3.15-3.17 (1H, m), 3.52-3.54 (3H, m), 3.53 (3H, s), 4.00-4.02(1H, m), 5.02 (1H, dm, J=64.45 Hz), 7.03 (1H, s), 7.92 (1H, d, J=7.03Hz), 8.39 (1H, s).

[0386] IR (KBr, disk) v: 3352, 3095, 3051, 2939, 2837, 2787, 1716, 1699,1616, 1520, 1439, 1358, 1319, 1259, 1221 cm⁻¹.

[0387] Melting point: 213 to 215° C.

[0388] Specific rotation: [α]_(D) ^(24.7)=−38.46° (c 0.195, 0.1 mol/lNaOH)

[0389] Elemental analysis: As C₂₂H₂₆FN₃O₄; Calcd.: C 63.60%; H 6.31%; N10.11% Found: C 63.36%; H 6.31%; N 9.97%

EXAMPLE 12

[0390]5-amino-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1,4-dihydro-4-oxoguinoline-3-CarboxylicAcid

[0391] After adding3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine(690 mg, 2.25 mmol) and triethylamine (0.50 ml) to dried dimethylsulfoxide (4 ml),5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (250 mg, 850 μmol) was added thereto and heated under reflux in anoil bath of 70° C. for 24 hours under a nitrogen atmosphere. Afterconcentrating the reaction solution under a reduced pressure, theresidue was dissolved in chloroform (100 ml). After washing the organiclayer with a 10% aqueous citric acid solution (100 ml) and saturatedsaline solution (100 ml), the organic layer was dried over anhydroussodium sulfate. After filtering, the filtrate was concentrated under areduced pressure, and after adding dropwise concentrated hydrochloricacid (5 ml) to the residue while cooling with ice, it was stirred atroom temperature for 30 minutes. After adding 1 mol/l hydrochloric acid(2 ml) to the reaction solution and washing the yellow acidic aqueoussolution with chloroform (50 ml×3), the pH was adjusted to 12.0 with anaqueous sodium hydroxide solution. After adjusting the pH of the basicaqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction withchloroform (100 ml×3) was performed. After drying over anhydrous sodiumsulfate, the solvent was evapolated under a reduced pressure. Theresidue thus obtained was then purified by preparative chromatography(developed into the lower layer of a 7:3:1 mixture ofchloroform:methanol:water), purified further by recrystallization fromethanol, and then dried under a reduced pressure. 70.0 mg (20%) of thetitle compound was thereby obtained in the form of yellow crystals.

[0392]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.56-0.64(4H, m), 1.21-1.61(3H, m), 1.92-1.96 (1H, m), 2.22 (3H, s), 2.45 (3H, s), 2.68-2.73 (1H,m), 3.19-3.31 (3H, m), 3.59-3.66 (1H, m), 3.72-3.77 (1H, m), 4.76-4.78(0.5H, m), 4.98-5.01 (0.5H, m), 5.97 (1H, s), 8.55 (1H, d, J=3.66 Hz).

[0393] IR (KBr, disk) v: 3440, 3329, 3082, 3005, 2964, 2937, 2877, 1716,1620, 1549, 1506, 1437, 1404 cm⁻¹.

[0394] Melting point: 129 to 131° C.

[0395] Specific rotation: [α]_(D) ^(22.6)=−291.90° (c 0.285, 0.1 mol/lNaOH)

[0396] Elemental analysis: As C₂₁H₂₅FN₄O₃.0.25H₂O; Calcd.: C 63.07%; H6.62%; N 13.37% Found: C 62.89%; H 6.42%; N 13.27%

EXAMPLE 13

[0397]2,3-dihydro-3-(S)-methyl-10-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-CarboxylicAcid

[0398] After adding3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine(125 mg, 521 μmol) and triethylamine (0.50 ml) to dried dimethylsulfoxide (1 ml),10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylicacid (132 mg, 500 μmol) was added thereto and stirred while heating inan oil bath of 100° C. for 20 hours under a nitrogen atmosphere. Afterconcentrating the reaction solution under a reduced pressure, theresidue was dissolved in chloroform (100 ml). After washing the organiclayer with a 10% aqueous citric acid solution (50 ml) and saturatedsaline solution (50 ml), the organic layer was dried over anhydroussodium sulfate. After filtering, the filtrate was concentrated under areduced pressure, and after adding concentrated hydrochloric acid (3 ml)to the residue while cooling with ice, it was stirred at roomtemperature for 30 minutes. After adding water (3 ml) to the reactionsolution and washing the yellow acidic aqueous solution with chloroform(50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxidesolution. After adjusting the pH of the basic aqueous solution to 7.4with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3)was performed. After drying over anhydrous sodium sulfate, the solventwas evapolated under a reduced pressure. The residue thus obtained wasthen purified by recrystallization from ethanol-ammonia water and thendried under a reduced pressure. 135 mg (70%) of the title compound wasthereby obtained in the form of yellow crystals.

[0399]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.56-0.60 (4H, m), 1.45-1.50(1H, m), 1.52 (3H, d, J=6.59 Hz), 1.99-2.01 (1H, m), 2.32 (3H, s),2.86-2.88 (1H, m), 3.21-3.55 (4H, m), 4.22, 4.45 (each 1H, ABq, J=11.36Hz), 4.57-4.59 (1H, m), 7.04-7.08 (1H, m), 7.80 (1H, d, J=9.03 Hz), 8.32(1H, s).

[0400] Melting point: 227 to 229° C.

[0401] Specific rotation: [α]_(D) ²⁴⁷=−131.00° (c 0.200, 0.1 mol/l NaOH)

[0402] Elemental analysis: As C₂₁H₂₅N₃O₄; Calcd.: C 65.78%; H 6.57%; N10.96% Found: C 65.49%; H 6.55%; N 10.82%

EXAMPLE 14

[0403]7-[3-(R)-[1-(ethylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-CarboxylicAcid

[0404] After adding3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)amino]cyclopropyl]pyrrolidine(2.16 g, 8.40 mmol) and triethylamine (4 ml) to dried dimethyl sulfoxide(10 ml),7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (1.95 g, 7.00 mmol) was added thereto and heated under reflux in anoil bath of 100° C. for 51 hour under a nitrogen atmosphere. Afterconcentrating the reaction solution under a reduced pressure, theresidue was dissolved in chloroform (150 ml). After washing the organiclayer with a 10% aqueous citric acid solution (100 ml) and saturatedsaline solution (100 ml), the organic layer was dried over anhydroussodium sulfate. After filtering, the filtrate was concentrated under areduced pressure, and after adding dropwise concentrated hydrochloricacid (10 ml) to the residue while cooling with ice, it was stirred atroom temperature for 30 minutes. After adding 1 mol/l hydrochloric acid(20 ml) to the reaction solution and washing the yellow acidic aqueoussolution with chloroform (100 ml×5), the pH was adjusted to 12.0 with anaqueous sodium hydroxide solution. After adjusting the pH of the basicaqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction withchloroform (150 ml×4) was performed. After drying over anhydrous sodiumsulfate, the solvent was evapolated under a reduced pressure. Theresidue thus obtained was purified by recrystallization from ethanol andthen dried under a reduced pressure. 1.61 g (55%) of the title compoundwas thereby obtained in the form of yellow crystals.

[0405]¹H-NMR (400 MHz, 0.1 mol/l NaOD) δ: 0.57-0.63 (4H, m), 1.04 (3H,t, J=6.95 Hz), 1.19-1.25 (1H, m), 1.47-1.64 (2H, m), 1.97-1.98 (1H, m),2.40 (3H, s), 2.70-2.73 (2H, m), 2.86-2.87 (1H, m), 3.26-3.28 (3H, m),3.61-3.63 (1H, m), 4.02-4.05 (1H, m), 5.03 (1H, dm, J=64.11 Hz), 7.07(1H, d, J=9.26 Hz), 7.98 (1H, d, J=9.26 Hz), 8.43 (1H, d, J=3.41 Hz).

[0406] IR (KBr, disk) v: 3294, 2964, 2848, 1699, 1612, 1508, 1473, 1431,1396, 1389, 1350, 1308, 1261 cm⁻¹.

[0407] Melting point: 191 to 194° C.

[0408] Specific rotation: [α]_(D) ^(24.3)=−236.55° (c 0.145, 0.1 mol/lNaOH)

[0409] Elemental analysis: As C₂₃H₂₈FN₃O₃; Calcd.:. C 66.81%; H 6.83%; N10.16% Found: C 66.52%; H 6.86%; N 10.03%

EXAMPLE 15

[0410]1-(cyclopropyl)-8-methyl-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1,4-dihydro-4-oxoguinoline-3-CarboxylicAcid

[0411] After adding3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine(880 mg, 3.25 mmol) and triethylamine (11.0 ml) to dried dimethylsulfoxide (5 ml),1-cyclopropyl-7-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (425 mg, 1.63 mmol) was added thereto and heated under reflux in anoil bath of 70° C. for 38 hours under a nitrogen atmosphere. Afterconcentrating the reaction solution under a reduced pressure, theresidue was dissolved in ethyl acetate (200 ml). After washing theorganic layer with a 10% aqueous citric acid solution (100 ml), theorganic layer was dried over anhydrous sodium sulfate. After filtering,the filtrate was concentrated under a reduced pressure, and after addingdropwise concentrated hydrochloric acid (6 ml) to the residue whilecooling with ice, it was stirred at room temperature for 30 minutes.After adding 1 mol/l hydrochloric acid (12 ml) to the reaction solutionand washing the yellow acidic aqueous solution with chloroform (50ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxidesolution. After adjusting the pH of the basic aqueous solution to 7.4with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3)was performed. After drying over anhydrous sodium sulfate, the solventwas evapolated under a reduced pressure. The residue thus obtained wasthen purified by recrystallization from a mixed solvent ofmethanol/2-propanol, and then dried under a reduced pressure. 331 mg(53%) of the title compound was thereby obtained in the form of yellowcrystals.

[0412]¹H-NMR (400 MHz, CDCl₃) δ: 0.57-0.65 (1H, m), 0.87-0.92 (1H, m),0.97-1.04 (1H, m), 1.11-1.18 (1H, m), 1.28-1.34 (1H, m), 1.64-1.71 (1H,m), 1.99-2.021H, m), 2.45 (3H, s), 2.50 (3H, s), 2.71-2.76 (1H, m),3.32-3.36 (3H, m), 3.64-3.70 (1H, m), 4.01-4.05 (1H, m), 6.99 (1H, d,J=9.06 Hz), 8.131H, d, J=9.06 Hz), 8.85 (1H, s).

[0413] Melting point: 190 to 192° C.

[0414] Elemental analysis: As C₂₂H₂₇N₃O₃; Calcd.: C 69.27%; H 7.13%; N11.02% Found: C 69.00%; H 7.16%; N 10.96%

REFERENCE EXAMPLE 25

[0415] Ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate

[0416] Ethyl 1-acetylcyclopropanecarboxylate (200 g, 1.28 mol) wasdissolved in ethanol (1000 ml), and bromine (72.7 ml, 1.41 mol) wasadded dropwise while stirring and cooling with ice. After completion ofdripping, the temperature of the reaction solution was raised to 30° C.and stirring was performed for 2 hours. After adding water (1000 ml) tothe reaction solution while cooling with ice, it was concentrated undera reduced pressure was performed. After extracting the concentrate intoethyl acetate (750 ml×2), it was washed with a 10% aqueous sodiumthiosulfate solution (500 ml×2) and saturated sodium bicarbonate water(500 ml×2) in that order and then dried over anhydrous sodium sulfate.After filtering and concentrating the filtrate under a reduced pressure,291 g (97%) of the title compound was obtained as a yellow, oilysubstance.

[0417]¹H-NMR (400 MHz, CDCl₃) δ: 1.30 (3H, t, J=7.1 Hz), 1.60-1.63 (4H,m), 4.22 (2H, q, J=7.1 Hz), 4.49 (2H, s).

[0418] TLC: Rf=0.7 (n-hexane:ethyl acetate=3:1)

REFERENCE EXAMPLE 26 Diethylphosphonoacetic Acid

[0419] Ethyl diethylphosphonoacetate (10 g, 446 mmol) was dissolved inethanol (275 ml), and after adding dropwise a 2 mol/l aqueous sodiumhydroxide solution (275 ml, 550 mmol) while stirring and cooling withice, it was stirred at room temperature for 1 hour. The reactionsolution was then concentrated under a reduced pressure, and theconcentrate was made acidic by concentrated hydrochloric acid whilecooling with ice. Extractions into ethyl acetate (200 ml×4), chloroform(100 ml×2) and 5% methanol/chloroform (250 ml×2) were then performed.The combined organic layers were then dried over anhydrous sodiumsulfate, and after filtering, the filtrate was concentrated under areduced pressure. 89 g (quantitative) of the title compound was therebyobtained as a colorless, oily substance.

[0420]¹H-NMR (400 MHz, CDCl₃) δ: 1.35 (6H, t, J=6.8 Hz), 2.98 (2H, d,J=21.7 Hz), 4.19 (4H, q, J=6.8 Hz).

[0421] TLC: Rf=0.1 (chloroform:methanol=9:1)

REFERENCE EXAMPLE 27

[0422] Ethyl1-[2-[N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate

[0423] 1-(S)-phenylethylamine (12.1 g, 100 mmol) was dissolved inacetonitrile (120 ml), and an acetonitrile (50 ml) solution oftriethylamine (15.3 ml, 110 mmol) and ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate (23.5 g, 100 mmol) was added dropwise in whilestirring and cooling with ice. After completion of dripping, thereaction solution was stirred while cooling with ice for 1.5 hours. Thereaction solution was then poured into water (75 ml) and concentratedunder a reduced pressure. The concentrate was subjected to extractionwith diisopropyl ether (75 ml×2) and then washed with water (75 ml).After extracting the organic layer into 1 mol/l hydrochloric acid (100ml×2), the acidic aqueous solution was washed with ethyl acetate (100ml). After adding a 1 mol/l aqueous sodium hydroxide solution (100 ml)to this acidic aqueous solution and then further adding saturated sodiumbicarbonate water (100 ml), extraction with ethyl acetate (100 ml) wasperformed. The organic layer was then washed with water (100 ml) andsaturated saline solution (100 ml) in that order, and then dried overanhydrous sodium sulfate. After filtering and then concentrating thefiltrate under a reduced pressure, 18.6 g (68%) of the title compoundwas obtained as a pale-yellow, oily substance.

[0424]¹H-NMR (400 MHz, CDCl₃) δ: 1.17 (3H, t, J=7.1 Hz), 1.38 (3H, d,J=6.6 Hz), 1.48 (4H, s), 3.71 (1H, q, J=6.6 Hz), 3.86 (2H, d, J=2.0 Hz),4.10 (2H, q, J=7.1 Hz).

[0425] TLC: Rf=0.6 (n-hexane:ethyl acetate=1:1)

REFERENCE EXAMPLE 28

[0426] Ethyl1-[2-[N-(diethylphosphonoacetyl)-N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate

[0427] Method A:

[0428] Diethylphosphonoacetic acid (15.1 g, 76.8 mmol) was dissolved inanhydrous tetrahydrofuran (120 ml), and after adding1,1′-carbonyldiimidazole (13.7 g, 84.5 mmol) while cooling with ice, itwas stirred at room temperature for 1 hour. After adding an anhydroustetrahydrofuran (30 ml) solution of ethyl1-[2-[N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate (17.6 g,64.0 mmol) to the reaction solution while cooling with ice, it wasstirred at room temperature for 1 hour. After adding 1 mol/lhydrochloric acid (100 ml) and ethyl acetate (100 ml) to the reactionsolution and performing an extraction operation, the organic layer wasseparated. The aqueous layer was then subjected to extraction with ethylacetate (100 ml) and the combined organic layer was washed withsaturated sodium bicarbonate water (100 ml) and saturated salinesolution (100 ml) in that order, and then dried over anhydrous sodiumsulfate. After filtering and then concentrating the filtrate under areduced pressure, 28.7 g (99%) of the title compound was obtained as ayellow syrup.

[0429] Method B

[0430] Diethylphosphonoacetic acid (32.8 g, 166 mmol) was dissolved inanhydrous benzene (700 ml), and after adding N,N′-dimethylformamide (1ml), thionyl chloride (18.2 ml, 250 mmol) was added thereto and heatedunder reflux for 1.5 hours. After letting the reaction solution cool, itwas concentrated under a reduced pressure, and after adding driedtoluene (100 ml) thereto, its concentration under a reduced pressure wasperformed again. After repeating this operation 3 times, the concentratewas dissolved in anhydrous tetrahydrofuran (300 ml) and after addingdropwise an anhydrous tetrahydrofuran (300 ml) solution of ethyl1-[2-[N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate (45.7 g,166 mmol) and triethylamine (25.1 ml, 183 mmol) while stirring andcooling with ice, it was stirred while cooling with ice for 1.5 hoursand then stirred at room temperature for 2 hours. After adding 1 mol/lhydrochloric acid (300 ml) and ethyl acetate (300 ml) to the reactionsolution and performing an extraction operation, the organic layer wasseparated. The aqueous layer was then subjected to extraction with ethylacetate (300 ml) and the combined organic layer was washed withsaturated sodium bicarbonate water (300 ml) and saturated salinesolution (300 ml) in that order, and then dried over anhydrous sodiumsulfate. After filtering and then concentrating the filtrate under areduced pressure, 43.6 g (70%) of the title compound was obtained as ayellow syrup.

[0431]¹H-NMR (400 MHz, CDCl₃) δ: 1.14, 1.20 (3H, t, J=7.1 Hz), 1.29-1.68(13H, m), 2.85, 4.69 (2H, dd, J=9.5, 20.7 Hz), 3.18, 4.55 (2H, d, J=22.2Hz), 4.06-4.22 (6H, m), 5.42, 6.05 (1H, q, J=7.1 Hz), 7.26-7.37 (5H, m).

[0432] MS (m/z): 454 ([M+H])⁺

[0433] TLC: Rf=0.1 (n-hexane:ethyl acetate=1:1)

REFERENCE EXAMPLE 29

[0434]4-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]-3-pyrrolin-2-one

[0435] After dissolving ethyl1-[2-[N-(diethylphosphonoacetyl)-N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate(25.0 g, 55.2 mmol) in toluene (250 ml), tert-butoxypotassium (7.40 g,66.2 mmol) was added gradually while stirring and cooling with ice.After stirring the reaction solution for 15 minutes at room temperature,a 10% aqueous citric acid solution (250 ml) and ethyl acetate (250 ml)were added thereto, and after performing an extraction operation, theorganic layer was separated. The aqueous layer was then subject toextraction with ethyl acetate (250 ml), and after washing the combinedorganic layer with saturated sodium bicarbonate water (250 ml) andsaturated saline solution (250 ml) in that order, the organic layer wasdried over anhydrous sodium sulfate. After filtering, the filtrate wasconcentrated under a reduced pressure, the concentrate was applied to asilica gel chromatography, and 12.1 g (73%) of the title compound wasobtained as a orange syrup from an n-hexane:ethyl acetate=2:1 to 1:2eluate. The instrumental analysis data for this resulting compoundagreed with the data indicated in PCT/JP96/00208.

[0436]¹H-NMR (400 MHz, CDCl₃) δ: 1.18, (3H, t, J=7.2 Hz), 1.60-1.63 (7H,m), 3.80 (1H, dd, J=1.5, 9.0 Hz), 4.07-4.11 (2H, m), 4.13 (1H, d, J=9.0Hz), 5.55 (1H, q, J=7.1 Hz), 5.84 (1H, t, J=1.5 Hz), 7.24-7.36 (5H, m).

[0437] MS (m/z): 300 ([M+H])⁺

[0438] TLC: Rf=0.5 (n-hexane:ethyl acetate=1:1)

REFERENCE EXAMPLE 30

[0439]4-(S)-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]pyrrolidin-2-one

[0440]4-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]-3-pyrrolin-2-one(12.1 g, 40.5 mmol) was dissolved in ethyl acetate (120 ml), a 5%platinum carbon catalyst (water content: 50%, 2.4 g) was added thereto,and it was stirred at room temperature for 17 hours under a hydrogenatmosphere at atmospheric pressure. The reaction solution was thenfiltered through cellite (washed with ethyl acetate) and the filtratewas then concentrated under a reduced pressure. The concentrate wasapplied to a silica gel chromatography, and 9.00 g (74%) of the compoundof the title were obtained as a pale-yellow syrup from an n-hexane:ethylacetate=3:2 eluate. Further, 2.60 g (21%) of the diastereomer(4-(R)-isomer) of the title compound was obtained as a pale-yellowsyrup. The instrumental analysis data for this resulting compound agreedwith the data indicated in PCT/JP96/00208.

[0441] 4-(S)-isomer:

[0442]¹H-NMR (400 MHz, CDCl₃) 6:0.63-0.65 (2H, m), 1.13 (3H, t, J=7.1Hz), 1.12-1.19 (2H, m), 1.52 (3H, d, J=7.3 Hz), 2.17 (1H, dd, J=9.0,16.8 Hz), 2.46 (1H, dd, J=9.3, 16.3 Hz), 2.67-2.76 (2H, m), 3.47 (1H, t,J=8.3 Hz), 3.96-4.11 (2H, m), 5.51 (1H, q, J=7.3 Hz), 7.26-7.35 (5H, m).

[0443] TLC: Rf=0.45 (n-hexane:ethyl acetate=1:1)

[0444] 4-(R)-isomer:

[0445]¹H-NMR (400 MHz, CDCl₃) δ: 0.72-0.76 (2H, m), 1.18-1.24 (2H, m)1.21 (3H, t, J=7.1 Hz), 1.52 (3H, d, J=7.1 Hz), 2.27-2.32 (1H, m),2.44-2.52 (2H, m), 3.14 (2H, d, J=8.0 Hz), 4.10 (2H, q, J=7.1 Hz), 5.50(1H, q, J=7.1 Hz), 7.26-7.35 (5H, m).

[0446] TLC: Rf=0.5 (n-hexane:ethyl acetate=1:1)

REFERENCE EXAMPLE 31

[0447]1-[1-[1-(S)-phenylethyl]-2-one-4-(S)-pyrrolidin-4-yl]-1-CyclopropanecarboxylicAcid

[0448]4-(S)-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]pyrrolidin-2-one(10.5 g, 34.9 mmol) was dissolved in 70 ml of ethanol, and after addinga 1 mol/l aqueous sodium hydroxide solution (70 ml) while cooling withice, the reaction solution was stirred at room temperature for 15.5hours and then at 40° C. for 3 hours. After concentrating the reactionsolution under a reduced pressure, the remaining aqueous layer waswashed with ethyl acetate (70 ml). The aqueous layer was then madeacidic by concentrated hydrochloric acid while cooling with ice and thensubjected to extraction with chloroform (70 ml×3). The organic layer wasthen dried over anhydrous sodium sulfate, and after filtering, thefiltrate was concentrated under a reduced pressure. 9.40 g (99%) of thetitle compound was thereby obtained as white solids.

[0449]¹H-NMR (400 MHz, CDCl₃) δ: 0.72-0.74 (2H, m), 1.21-1.23 (2H, m),1.52 (3H, d, J=7.3 Hz), 2.17 (1H, dd, J=8.8, 16.8 Hz), 2.48 (1H, dd,J=9.5, 16.8 Hz), 2.66-2.78 (2H, m), 3.50 (1H, t, J=9.3 Hz), 5.51 (1H, q,J=7.3 Hz), 7.25-7.34 (5H, m).

REFERENCE EXAMPLE 32

[0450]4-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidin-2-one

[0451] A toluene (15 ml) solution of triethylamine (9.6 ml, 69 mmol) anddiphenylphosphoric acid azide (DPPA; 10.4 g, 37.9 mmol) was added to atoluene (80 ml) suspension of1-[1-[1-(S)-phenylethyl]-2-one-4-(S)-pyrrolidin-4-yl]-1-cyclopropanecarboxylicacid (9.4 g, 34.4 mmol), and after stirring at room temperature for 1hour under a nitrogen atmosphere, it was heated under reflux for 1.5hours. After cooling the reaction solution to room temperature,tert-butyl alcohol (95 ml) was added thereto and heated under reflux for15 hours. After letting the reaction solution cool, the reactionsolution was concentrated under a reduced pressure and ethyl acetate (95ml) and water (95 ml) were added to the concentrate. After performing anextraction operation, the organic layer was separated and the aqueouslayer was subjected to extraction with ethyl acetate (95 ml). Thecombined organic layer was then washed with saturated saline solution(95 ml) and then dried over anhydrous sodium sulfate. After filteringand concentrating the filtrate under a reduced pressure, the concentratewas applied to a silica gel chromatography and 10.7 g (90%) of the titlecompound was obtained as a colorless, amorphous substance from achlorine:methanol=50:1 eluate.

[0452]¹H-NMR (400 MHz, CDCl₃) δ: 0.56-0.85 (4H, m), 1.37 (9H, s), 1.51(3H, d, J=7.3 Hz), 2.32-2.44 (3H, m), 2.79 (1H, dd, J=7.3, 10.0 Hz),3.36 (1H, m), 4.66 (1H, brs), 5.50 (1H, q, J=7.3 Hz), 7.26-7.34 (5H, m)

[0453] TLC: Rf=0.15 (n-hexane:ethyl acetate=1:1)

REFERENCE EXAMPLE 33

[0454]3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethyl]Pyrrolidine

[0455]4-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidin-2-one(10.4 g, 30.2 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml)and a 1.0M borane-tetrahydrofuran complex/tetrahydrofuran solution (90.7ml, 90.7 mmol) was added dropwise gradually thereto under a nitrogenatmosphere while cooling with ice. After completion of dripping, it wasstirred for 16 hours under the condition of from ice-cooling to roomtemperature. After slowly adding an aqueous solution (100 ml) ofpotassium carbonate (25.0 g, 181 mmol) to the reaction solution whilecooling with ice, it was heated under reflux was for 1.5 hours. Afterletting the reaction solution cool, it was extracted with ethyl acetate(100 ml×2) and then washed with saturated saline solution (100 ml) Theorganic layer was then dried over anhydrous sodium sulfate, and afterfiltering, the filtrate was concentrated under a reduced pressure. Theconcentrate was applied to a silica gel chromatography and 8.20 g (82%)of the title compound was obtained in the form of colorless crystalsfrom a chloroform:methanol=100:1 to 30:1 eluate.

[0456]¹H-NMR (400 MHz, CDCl₃) δ: 0.62 (2H, brs), 0.75-0.88 (2H, m), 1.35(3H, d, J=6.6 Hz), 1.41 (9H, s), 1.63 (2H, m), 1.88-1.92 (1H, m),2.14-2.17 (1H, m), 2.27-2.34 (2H, m), 2.63 (1H, brs), 3.15 (1H, t-like,J=6.6 Hz), 5.10 (1H, brs), 7.23-7.33 (5H, m).

[0457] MS (m/z): 331 ([M+H])⁺

[0458] TLC: Rf=0.4 (chloroform:methanol=9:1)

REFERENCE EXAMPLE 34

[0459] 3-(R)-[1-(tert-butoxycarbonylamino)Cyclopropyl]Pyrrolidine

[0460]3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidine(270 mg, 0.817 mmol) was dissolved in ethanol (15 ml), and after addinga 10% palladium carbon catalyst (water content: 52.0%; 270 mg), it wasstirred at 40° C. for 3 hours under a hydrogen atmosphere at atmosphericpressure. After removing the catalyst by filtering (ethanol washing),the filtrate was concentrated under a reduced pressure, and as a result,185 mg (quantitative) of the title compound was obtained in the form ofa colorless syrup.

[0461]¹H-NMR (400 MHz, CDCl₃) δ: 0.69 (2H, brs), 0.79 (2H, brs), 1.42(9H, s), 1.43-1.50 (1H, m), 1.86-1.88 (1H, m), 2.15-2.19 (1H, m),2.68-2.72 (1H, m), 2.90-3.07 (3H, m), 4.92 (1H, brs).

REFERENCE EXAMPLE 35

[0462]1-benzyloxycarbonyl-3-(R)-[1-(tert-butoxycarbonylamino)Cyclopropyl]Pyrrolidine

[0463]3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidine(1.70 g, 5.15 mmol) was dissolved in dichloromethane (34 ml), andbenzylchloroformate (1.10 ml, 7.73 mmol) was added dropwise whilestirring and cooling with ice. The reaction solution was then stirred atroom temperature for 2.5 hours and then stirred at 40° C. for 1.5 hours.After letting the reaction solution cool, the reaction solution wasconcentrated under a reduced pressure, the concentrate was applied to asilica gel chromatography, and 1.40 g (75%) of the title compound wasobtained in the form of a colorless syrup from an n-hexane:ethylacetate=2:1 eluate. The instrumental analysis data for this resultingcompound agreed with the data indicated in PCT/JP96/00208.

[0464]¹H-NMR (400 MHz, CDCl₃) δ: 0.70 (2H, brs), 0.80 (2H, brs), 1.41(9H, s), 1.63 (1H, m), 1.92 (1H, m), 2.25 (1H, m), 3.07-3.12 (1H, m),3.29-3.31 (1H, m), 3.56 (2H, m), 4.85 (1H, brs), 5.12 (2H, s), 7.33-7.36(5H, m).

[0465] TLC: Rf=0.4 (n-hexane:ethyl acetate=1:1)

REFERENCE EXAMPLE 36

[0466]1-benzyloxycarbonyl-3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)Amino]Cyclopropyl]Pyrrolidine

[0467]1-benzyloxycarbonyl-3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine(1.40 g, 3.89 mmol), N,N′-dimethylformamide (7 ml), silver oxide (9.0 g,39 mmol) and methyl iodide (24 ml, 389 mmol) were placed in a shaded andsealed tube, and this mixture was stirred for 13 hours in an oil bath of80° C. The reaction solution was then filtered through cellite (ethylacetate washing) and the filtrate was then diluted with ethyl acetate(100 ml). The organic layer was then washed with water (50 ml×3) andsaturated saline solution (50 ml) in that order, and dried overanhydrous sodium sulfate. After filtering, the filtrate was concentratedunder a reduced pressure, the concentrate was applied to a silica gelchromatography, and 1.31 g (89%) of the title compound was obtained inthe form of a pale-yellow syrup an n-hexane:ethyl acetate=2:1 eluate.The instrumental analysis data for this resulting compound agreed withthe data indicated in PCT/JP96/00208.

[0468]¹H-NMR (400 MHz, CDCl₃) δ: 0.83 (4H, brs), 1.42 (9H, s), 1.55 (1H,m), 1.88 (1H, m), 2.28-2.43 (1H, m), 2.83 (3H, s), 3.02-3.04 (1H, m),3.25-3.33 (1H, m), 3.55 (2H, m), 5.12 (2H, s), 7.32-7.35 (5H, m).

[0469] MS (m/Z): 374 ([M+H])⁺

[0470] TLC: Rf=0.4 (n-hexane:ethyl acetate=1:1)

REFERENCE EXAMPLE 37

[0471]3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)Amino]Cyclopropyl]Pyrrolidine

[0472]1-benzyloxycarbonyl-3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine(1.31 g, 3.48 mmol) was dissolved in ethanol (13 ml), and after adding a10% palladium carbon catalyst (water content: 50%; 0.65 g) thereto, itwas stirred at room temperature for 5 hours under a hydrogen atmosphereat atmospheric pressure. After performing filtration through cellite(ethanol washing), the filtrate was concentrated under a reducedpressure. As a result, 0.92 g (quantitative) of the title compound wasobtained in the form of a colorless syrup.

[0473]¹H-NMR (400 MHz, CDCl₃) δ: 0.80 (4H, brs), 1.46 (9H, s), 1.81 (1H,m), 2.04 (1H, brs), 2.28-2.42 (1H, m), 2.54 (1H, brs), 2.84 (3H, s),2.88-2.96 (3H, m).

[0474] TLC: Rf=0.1 (chloroform:methanol=9:1)

REFERENCE EXAMPLE 38

[0475]3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)Amino]Cyclopropyl]-1-[1-(S)-phenylethyl]Pyrrolidin-2-one

[0476]4-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidin-2-one(7.87 g, 22.8 mmol) was dissolved in dimethylformamide (100 ml), andwhile cooling with ice, 60% oily sodium hydride (10.10 g, 27.4 mmol) wasadded and stirred for 5 minutes. Then, methyl iodide (7.11 ml, 114 mmol)was added dropwise thereto while stirring at room temperature. Aftercompletion of dripping, the reaction suspension was stirred at roomtemperature for 14 hours. After adding 60% oily sodium hydride (296 mg,7.40 mmol) and methyl iodide (1.00 ml, 16.1 mmol), it was stirred at 40°C. for 24 hours. After adding a saturated aqueous ammonium chloridesolution (100 ml) and water (150 ml) to the reaction suspension whilestirring and cooling with ice, extraction with ethyl acetate (300 ml×2)was performed. The combined organic layer was then washed with water(100 ml×2) and saturated saline solution (100 ml×2) in that order, andthen dried over anhydrous sodium sulfate. After filtering, the filtratewas concentrated under a reduced pressure, the residue obtained wasapplied to a silica gel chromatography, and 7.53 g (92%) of the titlecompound was obtained in the form of a colorless oily substance from achloroform:methanol=50 to 30:1 eluate.

[0477]¹H-NMR (400 MHz, CDCl₃) δ: 0.83 (4H, m), 1.32 (6H, s), 1.38 (3H,s), 1.51 (3H, d, J=7.1 Hz), 1.61 (3H, d, J=16.6 Hz), 2.43 (1H, m),2.68-2.81 (3H, m), 3.21 (1H, m), 5.48-5.50 (1H, m), 7.26-7.36 (5H, m).

REFERENCE EXAMPLE 39

[0478]3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)Amino]Cyclopropyl]-1-[1-(S)-phenylethyl]Pyrrolidine

[0479]3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidin-2-one(7.53 g, 21.0 mmol) was dissolved in anhydrous tetrahydrofuran (70 ml)and a 1.0M borane-tetrahydrofuran complex/tetrahydrofuran solution (63.0ml, 63.0 mmol) was added dropwise gradually thereto while stirring andcooling with ice. After completion of dripping, it was stirred at roomtemperature for 20 hours. After slowly adding an aqueous solution (72ml) of potassium carbonate (7.22 g) while cooling with ice, it washeated under reflux for 1.5 hours. After letting the reaction solutioncool to room temperature, water (150 ml) was added, extraction withethyl acetate (200 ml×2) was performed, and then the combined organiclayer was washed with saturated saline solution (200 ml) and then driedover anhydrous sodium sulfate. After filtering, the filtrate wasconcentrated under a reduced pressure, the concentrate was applied to asilica gel chromatography, and 7.19 g (99%) of the title compound wasobtained in the form of a colorless syrup from achloroform:methanol=50:1 eluate.

[0480]¹H-NMR (400 MHz, CDCl₃) δ: 0.73 (4H, m), 1.35. (9H, s), 1.36 (3H,s), 1.61 (1H, m), 1.85 (1H, m), 1.97 (1H, m), 2.27 (1H, m), 2.50-2.58(2H, m), 2.79 (3H, s), 2.99 (1H, m), 3.14-3.19 (1H, m), 7.27-7.30 (5H,m).

REFERENCE EXAMPLE 40

[0481]3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)Amino]Cyclopropyl]Pyrrolidine

[0482]3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidine(7.19 g, 20.9 mmol) was dissolved in ethanol (78 ml), and after adding a10% palladium carbon catalyst (water content: 50%; 3.9 g), it wasstirred at 40° C. for 4 hours under a hydrogen atmosphere at atmosphericpressure. After performing filtration through cellite (ethanol washing),the filtrate was concentrated under a reduced pressure. As a result,4.38 g (quantitative) of the title compound was obtained in the form ofa colorless syrup. The ¹H-NMR data and the TLC Rf value of thisresulting compound agreed with the data indicated previously.

[0483]¹H-NMR (400 MHz, CDCl₃) δ: 0.80 (4H, brs), 1.46 (9H, s), 1.81 (1H,m), 2.04 (1H, brs), 2.28-2.42 (1H, m), 2.54 (1H, brs), 2.84 (3H, s),2.88-2.96 (3H, m).

[0484] TLC: Rf=0.1 (chloroform:methanol=9:1)

REFERENCE EXAMPLE 41

[0485]4-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)Amino]Cyclopropyl]-1-[1-(S)-phenylethyl]Pyrrolidin-2-one

[0486]4-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidin-2-one(4.16 g, 12.1 mmol) was dissolved in dimethylformamide (50 ml). Under anitrogen atmosphere and at room temperature, 60% oily sodium hydride(580 mg, 14.5 mmol) was added thereto and stirred for 10 minutes, andthen ethyl iodide (4.87 ml, 60.5 mmol) was added dropwise. Aftercompletion of dripping, the reaction suspension was stirred at roomtemperature for 15 hours. After adding a saturated aqueous ammoniumchloride solution (150 ml) to the reaction suspension while stirring andcooling with ice, extraction with ethyl acetate (150 ml×2) wasperformed. The combined organic layer was then washed with water (150ml×2) and saturated saline solution (150 ml) in that order, and thendried over anhydrous sodium sulfate. After filtering, the filtrate wasconcentrated under a reduced pressure, the residue obtained was appliedto a silica gel chromatography, and 4.56 g (quantitative) of the titlecompound was obtained in the form of a colorless oily substance from ann-hexane:ethyl acetate=1:2 eluate.

[0487]¹H-NMR (400 MHz, CDCl₃) δ: 0.49-0.80 (4H, m), 1.02-1.04 (3H, m),1.37 (9H, s), 1.49-1.51 (3H, m), 1.92-1.94 (1H, m), 2.04-2.06 (1H, m),2.36-2.38 (1H, m), 2.67-2.70 (2H, m), 3.20-4.23 (2H, m), 5.48-5.50 (1H,m), 7.26-7.52 (5H, m).

REFERENCE EXAMPLE 42

[0488]3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)Amino]Cyclopropyl]-1-[1-(S)-phenylethyl]Pyrrolidine

[0489]4-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)amino]cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidin-2-one(4.56 g, 12.1 mmol) was dissolved in anhydrous tetrahydrofuran (80 ml).,and a 1.0M borane-tetrahydrofuran complex/tetrahydrofuran solution (48.0ml, 48.0 mmol) was added dropwise in while stirring and cooling withice. After completion of dripping, the reaction solution was stirred for16 hours under the condition of from ice cooling to room temperature.After concentrating the reaction solution under a reduced pressure, a9:1 mixed solution (100 ml) of ethanol and water was added thereto, andafter adding triethylamine (5 ml), it was heated under reflux for 4hours. After cooling the reaction solution to room temperature,concentration was performed under a reduced pressure, saturated sodiumbicarbonate water (100 ml) was added to the residue, extraction withchloroform (100 ml×2) was performed, and then the combined organic layerwas washed with saturated saline solution (100 ml) and then dried overanhydrous sodium sulfate. After filtering, the filtrate was concentratedunder a reduced pressure, the concentrate was applied to a silica gelchromatography, and 4.26 g (99%) of the title compound was obtained inthe form of a colorless syrup from a chloroform:methanol=100:1 to 95:5eluate.

[0490]¹H-NMR (400 MHz, CDCl₃) δ: 0.54-0.78 (4H, m), 1.09-1.11 (3H, m),1.33-1.43 (13H, m), 1.84-1.97 (2H, m), 2.26-2.28 (2H, m), 2.56-2.57 (2H,m), 2.86-2.96 (1H, m), 3.13-3.18 (2H, m), 7.21-7.30 (5H, m).

REFERENCE EXAMPLE 43

[0491]3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)Amino]Cyclopropyl]Pyrrolidine

[0492]3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)amino]cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidine(3.01 g, 8.40 mmol) was dissolved in ethanol (120 ml), and after addinga 10% palladium carbon catalyst (water content: 50%; 3.0 g), it wasstirred at 40° C. for 5 hours under a hydrogen atmosphere at atmosphericpressure. After performing filtration through cellite (ethanol washing),the filtrate was concentrated under a reduced pressure. As a result,2.16 g (quantitative) of the title compound was obtained in the form ofa colorless syrup.

[0493]¹H-NMR (400 MHz, CDCl₃) δ: 0.83-0.85 (4H, m), 1.46 (9H, s),1.74-1.82 (1H, m), 2.16-2.18 (2H, m), 2.43-2.52 (2H, m), 2.90-2.99 (2H,m), 3.21-3.24 (2H, m).

REFERENCE EXAMPLE 44

[0494] 2,3,4-trichlorobenzoic Acid

[0495] Sodium hydroxide (45.42 g, 1.090 mol) was dissolved in water (220ml), and while cooling with ice, bromine (16.85 ml, 0.327 mol) wasdripped therein over a period of 5 minutes. After stirring the reactionsolution at 0° C. for 15 minutes, a dioxane (220 ml) solution of2′,3′,4′-trichloroacetophenone (24.40 g, 0.109 mol) was dripped thereinat 0° C. over a period of 30 minutes. After stirring at room temperaturefor 14 hours, water (350 ml) was added and then washed withdichloromethane (350 ml). The aqueous layer obtained was gradually madeacidic with concentrated hydrochloric acid while cooling with ice andthe resulting crystals were filtered out. After washing the filtered-outcrystals with water, the water was removed by azeotropic distillationwith toluene. 22.33 g (91%) of the title compound was thereby obtainedas a pale yellow powder.

[0496]¹H-NMR (400 MHz, CDCl₃) δ: 7.58 (1H, d, J=8.3 Hz), 7.70 (1H, d,J=8.6 Hz)

REFERENCE EXAMPLE 45

[0497] Ethyl (2,3,4-trichlorobenzoyl)Acetate

[0498] 2,3,4-trichlorobenzoic acid (4.51 g, 20.0 mmol) was dissolved intetrahydrofuran (80 ml), carbonyldiimidazole (3.89 g, 24.0 mmol) wasadded thereto while cooling with ice, and then stirred at roomtemperature for 3 hours (solution A). Meanwhile, malonic acid monoethylester monopotassium salt (6.81 g, 40.0 mmol) was suspended in ethylacetate, and while cooling with ice, triethylamine (13.9 ml, 100.0 mmol)and magnesium chloride (5.71 g, 60.0 mmol) were added thereto. Afterstirring at room temperature for 3 hours, the reaction solution wascooled with ice and the above-described solution A was dripped into thisreaction solution over a period of 10 minutes. After then washingsolution A into the reaction solution using tetrahydrofuran (10 ml), itwas stirred at room temperature for 14 hours, and then the reactionsolution was poured into a 10% aqueous citric acid solution (200 ml).This was then extracted with ethyl acetate (200 ml), washed withsaturated saline solution (200 ml), and then dried over anhydrous sodiumsulfate. After then removing the drying agent by filtration, the solventwas evapotated under a reduced pressure, and the crude product obtainedwas subject to silica gel chromatography, thereby obtaining 2.681 g(45%) of the title compound as a pale-red oil from an n-hexane:ethylacetate=5:1 eluate.

[0499]¹H-NMR (400 MHz, CDCl₃) δ: 1.25 (1.5H, t, J=7.2 Hz), 1.34 (1.5H,t, J=7.0 Hz), 3.99 (1H, s), 4.19 (1H, q, J=7.2 Hz), 4.28 (1H, q, J=7.0Hz), 5.47 (0.5H, s), 7.37-7.49 (2H, m), 12.45 (0.5H, m)

REFERENCE EXAMPLE 46

[0500] Ethyl7,8-dichloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate

[0501] A mixture of ethyl (2,3,4-trichlobenzoyl)acetate (2.681 g, 9.07mmol), acetic anhydride (10 ml) and triethyl orthoformate (20 ml) washeated under reflux for 2.5 hours in an oil bath at 140° C. Afterevaporationg the solvent under a reduced pressure, azeotropicdistillation was carried out using toluene (3 times) to obtain 3.272 gof a crude ethyl 3-ethoxy-2-(2,3,4-trichlorobenzoyl)acrylate as apale-red oil.

[0502] The above-obtained crude ethyl3-ethoxy-2-(2,3,4-trichlorobenzoyl)acrylate product (3.272 g) wasdissolved in dichloromethane (50 ml),2-(S)-fluoro-1-(R)-cyclopropylamine tosylate (2.467 g, 9.98 mmol) andtriethylamine (1.64 ml, 11.79 mmol) were added thereto in that orderwhile cooling with salted ice, and stirred at room temperature for 19.5hours. Ethyl acetate (200 ml) was added to the reaction solution, andafter washing with 10% aqueous citric acid solution (80 ml×2), saturatedaqueous sodium bicarbonate solution (80 ml) and saturated salinesolution (80 ml), it was dried over anhydrous sodium sulfate. After thenremoving the drying agent by filtration, the solvent was evapotatedunder a reduced pressure to obtain a crude ethyl3-[2-(S)-fluoro-1-(R)-cyclopropyl]amino-2-(2,3,4-trichlorobenzoyl)acrylate(3.59 g) as a pale-orange, gum-like substance.

[0503] The above-obtained crude ethyl3-[2-(S)-fluoro-1-(R)-cyclopropyl]amino-2-(2,3,4-trichlorobenzoyl)acrylate(3.57 g) was dissolved in dried dioxane (45 ml), and after adding sodiumhydride (60% content, 433 mg, 10.82 mmol) while cooling with ice, it wasstirred for 14 hours while heating in an oil bath at 50° C. Afterevaporationg the solvent under a reduced pressure, the residue wasdissolved in chloroform (150 ml), and after washing with 10% aqueouscitric acid solution (50 ml) and saturated saline solution (50 ml), itwas dried over anhydrous sodium sulfate. After then removing the dryingagent by filtration, the solvent was evaporated under a reduced pressuedpressure, and the crude product obtained was subject to silica gelchromatography, thereby obtaining 1.475 g (48%) of the title compound asa pale-yellow powder from a chloroform:ethyl acetate=1:2 eluate.

[0504]¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.50 (1H, m), 1.41 (3H, t, J=7.1Hz), 1.55-1.75 (1H, m), 4.08-4.13 (1H, m), 4.39 (2H, q, J=7.1 Hz),4.80-4.98 (1H, m), 7.53 (1H, d, J=8.5 Hz), 8.34 (1H, d, J=6.8 Hz), 8.57(1H, d, J=2.7 Hz).

[0505] MS (m/z): 344 (M⁺).

REFERENCE EXAMPLE 47

[0506]7,8-dichloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-CarboxylicAcid

[0507] A mixture of ethyl7,8-dichloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate(1.114 g, 3.237 mmol), acetic acid (8 ml) and concentrated hydrochloricacid (4 ml) was heated under reflux for 2 hours in an oil bath at 130°C. After then adding water (40 ml) and cooling with ice, the crystalsformed were filtered out and washed with water (5 ml×2), 5% aqueousethanol solution (5 ml×2), and diethyl ether (5 ml×2), thereby obtaining909 mg (89%) of the title compound as a pale-yellow powder.

[0508]¹H-NMR (400 MHz, CDCl₃) δ: 1.40-1.80 (2H, m), 4.23-4.28 (1H, m),4.83-5.02 (1H, m), 7.67 (1H, d, J=8.8 Hz), 8.38 (1H, d, J=8.6 Hz), 8.86(1H, d, J=2.7 Hz)

[0509] Melting point: 198 to 201° C.

[0510] Specific rotation: [α]_(D) ^(24.5)=−24.0°

[0511] Elemental analysis: As C₁₃H₈Cl₂FNO₃; Calcd.: C 49.39%; H 2.55%; N4.43% Found: C 49.14%; H 2.40%; N 4.33%

[0512] MS (m/z): 315 (M⁺), 354 [(M+K)⁺]

EXAMPLE 16

[0513]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-8-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-CarboxylicAcid

[0514] A mixture of 7,8-dichloro-1-[2-(S)-fluoro-1-(R)-140° C.cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (253 mg, 0.80mmol), 3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (272mg, 1.20 mmol), N-methyl piperidine (0.195 ml, 1.60 mmol) and dimethylsulfoxide (3 ml) was stirred for 55 hours while heating in an oil bathat 80° C. and under a nitrogen-replaced atmosphere. After evaporatingthe solvent, the residue was partitioned in ethyl acetate (50 ml) and10% aqueous citric acid solution (30 ml), and after separating theorganic layer, the organic layer was washed with saturated salinesolution (30 ml). The organic layer thus obtained was dried overanhydrous sodium sulfate, and after removing the drying agent byfiltration, the solvent was evaporated under a reduced pressure. Theresidue was subject to silica gel chromatography and a crude7-{3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidin-1-yl}-8-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid was obtained from a chloroform:methanol=10:1 eluate.

[0515] The above-obtained crude7-{3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidin-1-yl}-8-chloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid was dissolved in concentrated hydrochloric acid (5 ml) whilecooling with ice, and after stirring at room temperature for 20 minutes,the solution was transferred into a separation funnel and washed withchloroform (10 ml×10 times or more). Saturated aqueous sodium hydroxidesolution was then added while cooling with ice to the aqueous layerafter washing, thereby adjusting the pH to >11, and thereafter, the pHwas adjusted to 7.7 by adding concentrated hydrochloric acid and 1 mol/lhydrochloric acid. The aqueous layer obtained was then subject toextraction into chloroform (100 ml) and chloroform:methanol=9:1 (100ml×2), and the combined organic layer was dried over anhydrous sodiumsulfate. After removing the drying agent by filtration, the solvent wasevaporated under a reduced pressure. The residue was then purified by apreparative chromatography (developed into the lower layer of a 7:3:1mixture of chloroform:methanol:water), slurry-purified usingethanol-diethyl ether, and then dried under a reduced pressure to obtain96 mg (30%) of the title compound as a pale-yellow powder.

[0516]¹H-NMR (400 MHz, 0.1 mol/l NaOD/D₂O) δ: 0.45-0.65 (4H, m),1.15-1.30 (1H, m), 1.50-1.75 (2H, m), 2.00-2.10 (1H, m), 2.10-2.25 (1H,m), 3.25-3.40 (2H, m), 3.55-3.75 (2H, m), 4.10-4.15 (1H, m), 4.90-5.15(1H, m), 7.05 (1H, d, J=9.0 Hz), 7.99 (1H, d, J=9.3 Hz), 8.39 (1H, d,J=3.7 Hz).

[0517] Melting point: 128 to 130° C.

[0518] Specific rotation: [α]_(D) ^(24.5)=−193.0°

[0519] Elemental analysis: As C₂₀H₂₁ClFN₃O₃ .1.5H₂O: Calcd.: C 55.49%; H5.59%; N 9.71% Found: C 55.74%; H 5.45%; N 9.57%

[0520] MS (m/z): 406[(M+H)⁺]

REFERENCE EXAMPLE 48

[0521] Ethyl7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoguinoline-3-carboxylate

[0522] Ethyl5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate(1.414 g, 4.39 mmol) was suspended in 35% aqueous sulfuric acid solution(15 ml), and while cooling with ice, an aqueous sodium nitrite solution(394 mg, 5.70 mmol/4.5 ml) was dripped therein over a period of 5minutes. After then stirring at 0° C. for 30 minutes, a small amount ofurea was added, and at the same temperature, an aqueous copper (II)nitrate trihydrate solution (17.00, 70.2 mmol/155 ml) was drippedtherein over a period of 10 minutes. After stirring at 0° C. for 5minutes, copper (I) oxide (565 mg, 3.95 mmol) was added while stirringthe reaction solution violently. After then stirring at room temperaturefor 20 minutes, extraction into chloroform (200 ml×2) was performed, andafter making the aqueous layer slightly basic with sodium bicarbonate,the aqueous layer was extracted with chloroform (150 ml×3). The combinedorganic layer was then dried over anhydrous sodium sulfate, and afterremoving the drying agent bt the filtration, the solvent was evaporatedunder a reduced pressure. The crude product obtained was then subject toa silica gel chromatography, thereby obtaining 297 mg (21%) of the titlecompound as a yellow powder from a chloroform:methanol=10:1 eluate.

[0523]¹H-NMR (400 MHz, CDCl₃) δ: 1.36-1.47 (1H, m), 1.40 (3H, t, J=7.1Hz), 1.53-1.63 (1H, m), 2.51 (3H, t, J=2.4 Hz), 3.85-3.90 (1H, m), 4.39(2H, q, J=7.2 Hz), 4.77-4.96 (1H, m), 6.58 (1H, d, J=11.5 Hz), 8.52 (1H,d, J=3.2 Hz).

[0524] MS (m/z): 324 [(M+H)⁺]

REFERENCE EXAMPLE 49

[0525]7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-CarboxylicAcid

[0526] A mixture of ethyl7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate(325 mg, 1.005 mmol), acetic acid (3 ml) and concentrated hydrochloricacid (1.5 ml) was heated under reflux for 2 hours in an oil bath at 120°C. After then adding water (30 ml) and cooling with ice, the crystalsformed were filtered out and then washed with water, 5% aqueous ethanolsolution, and diethyl ether to obtain 267 mg (90%) of the title compoundas a pale-yellow powder.

[0527]¹H-NMR (400 MHz, CDCl₃) δ: 1.40-1.75 (2H, m), 2.58 (3H, t, J=2.5Hz), 3.99-4.04 (1H, m), 4.80-5.05 (1H, m), 6.70 (1H, d, J=11.3 Hz), 8.76(1H, d, J=3.2 Hz), 13.17 (0.7H, d, J=1.0 Hz), 13.34 (0.7H, brs).

[0528] Melting point: 209 to 213° C.

[0529] Specific rotation: [α]_(D) ^(24.7)=−111.6°

[0530] Elemental analysis: As C₁₄H₁₁F₂NO₄: Calcd.: C 56.95%; H 3.76%; N4.74% Found: C 56.90%; H 3.74%; N 4.68%

[0531] MS (m/z): 296[(M+H)⁺]

EXAMPLE 17

[0532]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-CarboxylicAcid

[0533] A mixture of7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (205 mg, 0.694 mmol),3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (314 mg,1.388 mmol), N-methyl piperidine (0.243 ml, 1.388 mmol), and dimethylsulfoxide (1.5 ml) was stirred for 66 hours while heating in an oil bathat 80° C. under a nitrogen-replaced atmosphere. After evaporating thesolvent, the residue was partitioned in chloroform (50 ml) and 10%aqueous citric acid solution (30 ml), and after separating the organiclayer, the aqueous layer was further subject to extraction intochloroform (30 ml). The combined organic layer was then dried overanhydrous sodium sulfate, and after removing the drying agent byfiltration, the solvent was evaporated under a reduced pressure tothereby obtain a crude7-{3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidin-1-yl}-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.

[0534] The above obtained crude7-{3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidin-1-yl}-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid was dissolved in concentrated hydrochloric acid (20 ml) whilecooling with ice, and after stirring at room temperature for 20 minutes,the solution was transferred into a separation funnel and washed withchloroform (20 ml×5 times). Saturated aqueous sodium hydroxide solutionwas then added while cooling with ice to the aqueous layer afterwashing, thereby adjusting the pH to >11, and thereafter, the pH wasadjusted to 7.5 to 7.8 by adding concentrated hydrochloric acid and 1mol/l hydrochloric acid. The aqueous layer obtained was then subject toextraction into chloroform (100 ml), chloroform:methanol=9:1 (100 ml×2),and the lower layer of chloroform:methanol:water=7:3:1 (100 ml), and thecombined organic layer was dried over anhydrous sodium sulfate. Afterremoving the drying agent by filtration, the solvent was evaporatedunder a reduced pressure. The residue was then purified by a preparativechromatography (developed into the lower layer of a 7:3:1 mixture ofchloroform:methanol:water), slurry-purified using diethyl ether, andthen dried under a reduced pressure to obtain 119 mg (43%) of the titlecompound as a yellow powder.

[0535]¹H-NMR (400 MHz, 0.1 mol/l NaOD/D₂O) δ: 0.45-0.55 (4H, m),1.05-1.20 (1H, m), 1.45-1.70 (2H, m), 1.90-2.00 (1H, m), 2.05-2.20 (1H,m), 2.16 (3H, s), 3.05-3.20 (2H, m), 3.25-3.35 (1H, m), 3.40-3.50 (1H,m), 3.90-3.95 (1H, m), 4.90-5.10 (1H, m), 6.16 (1H, s), 8.33 (1H, d,J=3.4 Hz).

[0536] Melting point: 203-206° C.

[0537] Specific rotation: [α]_(D) ^(25.1)=−274.4°

[0538] Elemental analysis: As C₂₁H₂₄FN₃O₄.1.5H₂O: Calcd: C 58.87%; H6.35%; N 9.81% Found: C 59.23%; H 6.20%; N 9.48%

[0539] MS (m/z): 402[(M+H)⁺]

EXAMPLE 18

[0540]7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-8-cyano-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-CarboxylicAcid

[0541] A mixture of ethyl8-cyano-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate(250 mg, 0.785 mmol),3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (267 mg, 1.18mmol), 1,4-diazabicyclo[2.2.2]octane (132 mg, 1.18 mmol), and dimethylsulfoxide (13 ml) was stirred for 2 hours at room temperature under anitrogen-replaced atmosphere. After evaporating the solvent, the residuewas partitioned in chloroform (30 ml) and 10% aqueous citric acidsolution (30 ml), and the organic layer was separated. The organic layerobtained was dried over anhydrous sodium sulfate, and after removing thedrying agent by filtration, the solvent was evaporated under a reducedpressure. The residue was dissolved in concentrated hydrochloric acid (4ml) and glacial acetic acid (4 ml) at room temperature and then stirredfor 12 hours while heating in an oil bath at 110° C. After evaporatingthe solvent, concentrated hydrochloric acid (2 ml) and water (20 ml)were added, and the solution was transferred into a separation funneland then washed with chloroform (50 ml). 10 mol/l Aqueous sodiumhydroxide solution was then added to the aqueous layer after washing,thereby adjusting the pH to >12. Then after washing with chloroform (50ml), the pH was adjusted to 8.3 by adding concentrated hydrochloric acidand 1 mol/l hydrochloric acid. The aqueous layer obtained was thenconcentrated to 5 ml under a reduced pressure, subject to extractioninto chloroform:methanol=10:1 (50 ml×3), and the combined organic layerwas dried over anhydrous sodium sulfate. After removing the drying agentby filtration, the solvent was evaporated under a reduced pressure. Theyellow solids thus obtained were recrystallized in ethanol and thendried under a reduced pressure to obtain 124 mg (40%) of the titlecompound as a yellow powder.

[0542]¹H-NMR (400 MHz, DMSO-d₆) δ: 0.48-0.51 (4H, m), 1.66-1.90 (3H, m),1.99-2.03 (1H, m), 2.03-2.09 (1H, m), 3.57-3.70 (3H, m), 3.79-3.83 (1H,m), 4.03-4.08 (1H, m), 5.18-5.35 (1H, m), 7.14 (1H, d, J=9.3 Hz), 8.16(1H, d, J=9.3 Hz), 8.61 (1H, d, J=3.9 Hz).

[0543] Melting point: 138 to 140° C.

[0544] Specific rotation: [α]_(D) ^(24.5)=+19.16°

[0545] Elemental analysis: As C₂₁H₂₁FN₄O₃.1.25H₂O: Calcd: C 60.21%; H5.65%; N 13.07% Found: C 60.42%; H 5.62%; N 12.72%

[0546] MS (m/z): 397[(M+H)⁺]

EXAMPLE 19

[0547]7-[3-(R)-(1-aminocyclobutyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-CarboxylicAcid

[0548] A mixture of7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (290 mg, 0.98 mmol),3-(R)-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrrolidine (283 mg, 1.18mmol), triethylamine (0.409 ml, 2.94 mmol), and dimethyl sulfoxide (5ml) was stirred for 112 hours while heating in an oil bath at 80° C.under an argon-replaced atmosphere. After evapotating the solvent, theresidue was partitioned in chloroform (50 ml) and 10% aqueous citricacid solution (30 ml), and after separating the organic layer, theorganic layer was washed with saturated saline solution (30 ml). Theorganic layer obtained was then dried over anhydrous sodium sulfate, andafter removing the drying agent by filtration, the solvent wasevaporated under a reduced pressure. The residue was subject to a silicagel chromatography and a crude7-{3-(R)-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrrolidin-1-yl}-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid was thereby obtained from a chloroform:methanol=20:1 eluate.

[0549] The above obtained crude7-{3-(R)-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrrolidin-1-yl}-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid was dissolved in concentrated hydrochloric acid (5 ml) whilecooling with ice, and after stirring for 5 minutes in an ice-water bath,the solution was transferred into a separation funnel and washed withchloroform (10 ml×3 times). 10 mol/l Aqueous sodium hydroxide solutionwas then added while cooling with ice to the aqueous layer afterwashing, thereby adjusting the pH to >12, and thereafter, the pH wasadjusted to 7.4 by adding concentrated hydrochloric acid and 1 mol/lhydrochloric acid. The aqueous layer obtained was then subject toextraction into chloroform (100 ml×3) and the combined organic layer wasdried over anhydrous sodium sulfate. After removing the drying agent byfiltration, the solvent was evapotaed under a reduced pressure. Theresidue was then recrystallized in ethyl acetate-hexane and dried undera reduced pressure 99 mg (24%) of the title compound as a yellow powder.

[0550]¹H-NMR (400 MHz, d₆-DMSO) δ: 1.30-1.45 (1H, m), 1.45-1.60 (1H, m),1.60-1.70 (1H, m), 1.70-2.50 (8H, m), 3.30-3.40 (1H, m), 3.40-3.50 (1H,m), 3.50 (3H, s), 3.56-3.60 (2H, m), 4.03-4.09 (1H, m), 5.00-5.22 (1H,m), 7.09 (1H, d, J=9.1 Hz), 7.92 (1H, d, J=9.1 Hz), 8.57 (1H, d, J=3.4Hz).

[0551] Melting point: 174° C.

[0552] Elemental analysis: As C₂₂H₂₆FN₃O₄.0.25H₂O: Calcd: C 62.92%; H6.36%; N 10.01% Found: C 63.20%; H 6.22%; N 10.10%

[0553] MS (m/z): 416[(M+H)⁺]

REFERENCE EXAMPLE 50

[0554] 3-cyano-2,4-Difluorobenzoic Acid

[0555] After dissolving diisopropylamine (56.0 ml, 395 mmol) inanhydrous tetrahydrofuran (400 ml), the solution was stirred at −15° C.under a nitrogen atmosphere. After dripping therein a hexane solution ofn-butyllithium (1.52M, 260 ml, 395 mmol), the solution was stirred whilecooling with ice for 1 hour. After cooling this solution to −78° C., asolution, in which 2,6-difluorobenzonitrile (25.0 g, 180 mmol) wasdissolved in anhydrous tetrahydrofuran (100 ml), was dripped thereinover a period of 1 hour. After completion of dripping, the reactionsolution was stirred at −78° C. for 1 hour and then dried carbon dioxidewas bubbled into this reaction solution for 30 minutes. Thereafter, thereaction solution was stirred at −78° C. for 1 hour, then raisedgradually in temperature, and then stirred at room temperature for 12hours. 100 ml of 1 mol/l Hydrochloric acid was then added to thereaction solution while cooling with ice and extraction into diethylether (500 ml×2) was performed. The combined organic layer was washedwith saturated saline solution (500 ml) and then dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated under areduced pressure, thereby obtaining 29.7 g (90%) of the yellow,amorphous compound of the title. This product was used in the subsequentreaction without further purification.

[0556]¹H-NMR (400 MHz, CDCl₃) δ: 7.10 (1H, m), 8.32 (1H, m)

REFERENCE EXAMPLE 51

[0557] Ethyl8-cyano-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoguinoline3-carboxylate

[0558] 3-cyano-2,4-difluorobenzoic acid (29.6 g, 162 mmol) was dissolvedin dried toluene (250 ml), and after adding a catalytic amount ofN,N-dimethylformamide, thionyl chloride (17.7 ml, 243 mmol) was drippedin while stirring at room temperature. Upon completion of dripping, thereaction solution was stirred for 1 hour in an oil bath at 80° C. Thenafter letting the reaction solution cool, the reaction solution wasconcentrated under a reduced pressure, toluene (100 ml) was added to theresidue, and vacuum concentration was performed again. This operationwas repeated 3 times. The concentrate thus obtained was dissolved inanhydrous tetrahydrofuran (200 ml), and this solution was dripped, whilestirring and cooling with ice, into a solution, in which triethylamine(30 ml) and ethyl 3-dimethylaminoacrylate (24.3 g, 170 mmol) weredissolved in anhydrous tetrahydrofuran (100 ml). After completion ofdripping, the reaction solution was heated under reflux for 12 hours.After then filtering the reaction solution through cellite (washing withdiethyl ether), the filtrate was concentrated under reduced pressure andthe residue obtained was subject to a short silica gel chromatography. Abrown, oily substance was then obtained by vacuum concentration of achloroform:methanol=100:1 to 100:3 eluate.

[0559] This substance was then dissolved in anhydrous tetrahydrofuran(300 ml), 2-(S)-fluoro-1-(R)-cyclopropylamine paratoluenesulfonate (28.2g, 114 mmol) was added thereto, and while stirring at −15° C., asolution, in which triethylamine (23 ml, 165 mmol) was dissolved inanhydrous tetrahydrofuran (50 ml), was dripped therein gradually. Aftercompletion of dripping, the reaction solution was stirred while coolingwith ice for 2 hours and then stirred at room temperature for 12 hours.Water (300 ml) was then added to the reaction solution, and vacuumconcentration was performed to evaporate the tetrahydrofuran. Water (300ml) was further added, and then extraction into ethyl acetate (400 ml×3)was performed. After washing the combined organic layer with saturatedsaline solution (500 ml), it was dried over anhydrous sodium sulfate.After filtration, the filtrate was concentrated under reduced pressure.A yellowish-brown, oily substance was thus obtained.

[0560] This substance was dissolved in a dried 1,4-dioxane (400 ml), andwhile stirring and cooling with ice, 60% oily sodium hydride (4.35 g)was added gradually. This reaction suspension was then stirred at roomtemperature for 1 hour. After then concentrating the reaction solutionto approximately ⅓rd the original volume under a reduced pressure, 0.5mol/l hydrochloric acid (50 ml) was poured in gradually while coolingwith ice. The precipitated solids were filtered out, washed with water,and then washed with small amounts of cold ethanol and diethyl ether, inthat order. The crude crystals obtained were purified byrecrystallization in isopropanol, and dried under a reduced pressure toobtain 10.6 g (49%) of the title compound as yellowish-white crystals.

[0561] Melting point: 172 to 177° C. (decomposed)

[0562]¹H-NMR (400 MHz, CDCl₃) δ: 1.23-1.30 (1H, m), 1.41 (3H, t, J=7.1Hz), 1.61-1.99 (1H, m), 4.00 (1H, m), 4.40 (2H, q, J=7.1 Hz), 5.10 (1H,dm, J=63.5 Hz), 7.31 (1H, m), 8.52 (1H, d, J=2.6 Hz), 8.77 (1H, m)

TEST EXAMPLE 1

[0563] Antibacterial activities of the compounds of this invention weremeasured in accordance to the standard method designated by the JapanSociety of Chemotherapy, with the results shown as MIC values(microgram/ml) units in the following table. For comparison with the MICvalues of the compounds of this invention, MIC values of levofloxacin(LVFX), ciprofloxacin (CPFX) and7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Reference drug 1), which is described in PCT/JP96/00208, are alsoshown in the table. TABLE 1 Example Example Example Example Example 1 23 10 11 E. coli, ≦0.003 ≦0.003 ≦0.003 ≦0.003 0.006 NIHJ S. flexneri,0.006 0.012 ≦0.003 0.006 0.012 2A 5503 Pr. vulgalis, ≦0.003 0.012 ≦0.0030.006 0.012 08601 K. 0.025 0.05 0.012 0.025 0.1 pneumoniae, Type 1 Ser.0.025 0.1 0.025 0.05 0.2 marcescens, 10100 Ps. 0.05 0.2 0.05 0.1 0.2aeruginosa, 32104 Ps. 0.025 0.05 0.025 0.025 0.1 aeruginosa, 32121 Ps.0.2 0.2 0.05 0.1 0.2 maltophilia, IID-1275 S. aureus, ≦0.003 ≦0.003≦0.003 ≦0.003 ≦0.003 209P S. ≦0.003 0.012 0.003 0.006 0.012 epidermidis,56500 Str. ≦0.003 0.006 0.003 ≦0.003 0.012 pyogenes, G-36 Str. faecalis,0.012 0.025 0.012 0.012 0.05 ATCC 19433 S. aureus, 0.05 0.05 0.025 0.0250.05 870307 Str. ≦0.003 0.006 ≦0.003 ≦0.003 0.006 pneumoniae J24 ExampleExample Reference 14 15 drug 1 LVFX CPFX E. coli, ≦0.003 ≦0.003 ≦0.0030.012 ≦0.003 NIHJ S. flexneri, 0.006 0.006 ≦0.003 0.025 0.006 2A 5503Pr. vulgalis, 0.012 0.012 ≦0.003 0.012 ≦0.003 08601 K. 0.05 0.025 0.0060.1 0.025 pneumoniae, Type 1 Ser. 0.1 0.1 0.012 0.1 0.025 marcescens,10100 Ps. 0.1 0.1 0.025 0.2 0.005 aeruginosa, 32104 Ps. 0.05 0.05 0.0120.1 0.025 aeruginosa, 32121 Ps. 0.2 0.2 ≦0.003 0.39 0.78 maltophilia,IID-1275 S. aureus, ≦0.003 ≦0.003 ≦0.003 0.2 0.1 209P S. 0.006 0.006≦0.003 0.39 0.2 epidermidis, 56500 Str. ≦0.003 ≦0.003 ≦0.003 0.2 1.56pyogenes, G-36 Str. faecalis, 0.025 0.025 0.006 0.78 0.78 ATCC 19433 S.aureus, 0.012 0.025 0.012 ≦6.25 3.13 870307 Str. ≦0.003 ≦0.003 ≦0.0030.78 0.1 pneumoniae J24

TEST EXAMPLE 2

[0564] For the compound described as Example 1 of this invention, themicronucleus test in bone marrow of mice was performed by the followingmethod.

[0565] Mice groups, each consisting of five, six-week-old, Slc:ddY malemice, were used. The compound of this invnetion described as Example 1and7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Reference drug 1) described in PCT/JP96/00208 were dissolved inand diluted with 0.1 mol/l NaOH/saline solution. The 0.1 mol/lNaOH/saline solvent was used as a control, and as a positive Referencedrug, a drug solution, prepared by dissolving and dilutingcyclophosphamide (CP) in saline solution, was used. All drug solutionswere disinfected by filtration through Mylex GS 0.22 μm filters. Witheach drug solution, a single intravenous dose of 10 ml/kg wasadministered at an administration rate of 0.2 ml/min. 24 hours afteradministration, myeloma cells were collected from the femur bone, thesmear preparations were prepared, and these were dyed with acrylicorange. Using a fluorescence microscope, 1000 polychromatic erythrocyteswere observed for each individual mouse, and the frequency of occurrenceof micronucleated polychromatic erythrocytes and the ratio oforthochromatic erythrocytes and polychromatic erythrocytes among 1000erythrocytes were calculated.

[0566] As a result, a significant difference in the micronucleusinduction rate was not seen between the control and any of the 25, 50,and 100 mg/kg administration groups for the compound described asExample land the judgment result was thus negative. That is, thecompound described as Example 1 was found to be extremely weak inmicronucleus induction and high in safety.

[0567] In contrast, with the comparison compound,7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Reference drug 1) described in PCT/JP96/00208, micronucleusinduction in comparison to the control was clearly seen with the 50 and100 mg/kg administration groups.

[0568] These results show that the compound described as Example 1 ofthis invention, wherein a fluorine atom of the 6-position of thecomparison compound,7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid described in PCT/JP96/00208 is replaced by a hydrogen atom,exhibits a potent antibacterial action upon a broad range of bothgram-negative bacteria and gram-positive bacteria, including resistantbacteria, and yet is high in safety.

TEST EXAMPLE 3

[0569] For the compound of this invention described as Example 1, theblood concentration and organ concentration after oral administrationwere determined by the following methods. Measurements were also made bythe same methods for Reference drug 1.

[0570] Method 1: Animal Tests

[0571] An administration solution was prepared by dissolving a testedcompound to a concentration of 2 mg/ml (as free compound) in distilledwater, and using a 2.5 ml disposable syringe or a metal oral probe, thesolution was orally administered at a dose of 20 mg/kg to fasting rats(Crj: CD IGS; male; 7-week-old; Charles River Japan, Inc.).

[0572] The absorption test groups (4 rats per group; total of 6 groups)were killed by exsanguination while under ether anesthetization 0.25,0.5, 1, 2, 4, or 6 hours after drug administration, and the blood,liver, kidneys, and lungs were sampled. With the blood, serum wassampled by centrifugation (3000 rpm×15 minutes, 4° C.) aftercoagulation. Tissues were homogenized after adding 3 to 5 ml of 0.1Mphosphate buffer solution (pH 7.0) and the centrifugation supernatants(3000 rmpm×15 minutes, 4° C.) were collected.

[0573] The excretion test groups (4 rats per group) were put in ametabolic cage after drug administration, and collected urine samplesfor 0 to 4 hours and 4 to 24 hours were sampled while cooling with ice,and at the time of sampling, the interior of the cage was washed withapproximately 15 ml of 0.1 mol/l phosphate buffer solution (pH 7.0) torecover the urine attached to the interior of the cage. Also in order toexamine glucuronide and other conjugated compounds, a part of the samplewas separated, hydrolyzed with an equivalent amount of 1 mol/l aqueoussodium hydroxide solution, and thereafter neutralized with 0.5 mol/lhydrochloric acid, and concentration measurements were made on samplesprepared in this manner.

[0574] Method 2: Drug Concentration Measurements

[0575] Determination of drug concentrations in liquid samples werequantified by an agar well method bioassay using the B. subtilisATCC6051 strain as the test organism. A test medium was prepared byinoculating a suspension containing 5×10⁷CFU/ml of spores of the testbacteria at a proportion of 1% into an nutrient agar (Eiken Kagaku) thatwas sterilized at 121° C. for 15 minutes and then cooled toapproximately 50° C. After placing 10 ml each of this medium in asterilized Petri dish and solidifying horizontally, four holes of 8 mmdiameter were made to prepare a test plate medium. The Bioassay SystemTDA-1 (Dainippon Seiki) was used for preparation of the test platemedia. For the measurements, the test samples (diluted with serum orphosphate buffer solution as necessary), serial dilutions of the drugsolutions for calibration (two-fold serial dilutions prepared so thatthe inhibition ring diameter will be approximately 10 to 30 mm), and areference drug solution (a drug solution of given concentration forcorrection of the error among plates; normally, a concentration offorming an inhibition ring of approximately 20 mm is used) wereprepared, and 50 μL of the test sample (or the drug solution forcalibration) were placed in each of two of the four holes of each plateand 50 μL of the reference solution was placed in each of the other twoholes. After addition of the sample, the plate medium was set still for1 hour at 4° C. to perform preliminary dispersion and then culturing at37° C. was performed for approximately 18 hours, and the inhibition ringdiameters were measured using CA-400 (Dainippon Seiki). Theconcentrations of the test samples were measured using a calibrationcurve determined by second-order regression from the logarithmic valuesof the drug concentration of the calibration curve serial dilutions andthe inhibition ring diameters.

[0576] For the tissue concentration (μg/ml), the concentration (μg/ml)in the homogenate supernatant was determined from the tissue weight (g)and the added phosphate buffer amount (ml) and using the followingequation:

[Tissue concentration]=[Homogenate concentration]×([Tissueweight]+[Buffer solution amount])/[Tissue weight]

[0577] The urinary excretion rate (%) was determined from the amount(μg) of drug administered, amount (ml) of urine (or washing solution),and concentration (μg/ml) in urine (or washing solution):

[Urinary excretion rate]=100×([Amount of urine]×[Concentration inurine])/[Amount of drug administered]

[0578] Method 3: Calculation of Pharmacokinetic Parameters

[0579] For each drug, the pharmacokinetic parameters in rats werecalculated based on mean concentration, by non-compartmental analysis,and using the pharmacodynamics analysis software, PSAG-CP (Asmedica).

[0580] The serum concentration and the organ concentration for liver,kidneys, and lungs of the compound of Example 1 and Reference drug 1,determined by the above methods, are shown in Table 2. TABLE 2 Compoundof Compound Example 1 (addition (1 HCl, 0.25 IPA, Reference Drugproduct) 0.25 H₂0) (1 MsOH, 1 H₂0) Serum C_(max)(μg/ml) 1.7 1.6 t_(1/2)(h) 1.2 1.0 AUC_(0-4 h) 3.1 2.3 (μg · h/ml) Tissue Liver 27.4 11.6C_(max)(μg/g) Kidney 14.2 5.0 Lung 3.8 3.0 Liver 34.5 (11.0) 10.4 (4.6)AUC_(0-4 h) Kidney 29.0 (9.2)   7.1 (3.1) (tissue/serum Lung 10.0 (3.2)  5.3 (2.3) ratio) Urinary 0-24 h 8.1 1.8 recovery after addition 8.7 2.3ratio of (per conjugated dose) compounds

[0581] As is apparent from Table 2, the compound of this invention wasfound to be distributed at higher concentrations, for both serum andtissue, in comparison to Reference drug 1. It is thus apparent that thecompound of this invention is excellent in oral absorption. It is alsoapparent that the compound of this invention is excellent in tissuepenetration.

[0582] The structures of the compounds that were compared in activitiesare as follows.

INDUSTRIAL APPLICABILITY

[0583] Compounds of this invention exhibit excellent antibacterialaction upon a broad range of both gram-negative and gram-positivebacteria and, in particular, exhibit potent antibacterial activity evenagainst resistant gram-positive bacteria, such as methicillin-resistantStaphylococcus aureus (MRSA), penicillin-resistant Streptococcuspneumoniae (PRSP), vancomycin-resistant Enterococcus (VRE), etc., andquinolone-resistant bacteria, and yet are excellent in safetycharacteristics, such as being negative in micronucleus tests, andexcellent in pharmacokinetics, such as being improved in urinaryrecovery rates and being excellent in oral absorption and tissuepenetration, etc. The compounds of this invention are thus useful asantibacterial compounds to be used in chemotherapy against microbialinfections.

1. A compound represented by the following general formula (I), itssalts, and hydrates thereof:

[wherein R¹ represents an alkyl group having 1 to 6 carbon atoms, analkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms,which may have a substituent, an aryl group, which may have asubstituent, a heteroaryl group, which may have a substituent, an alkoxygroup having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6carbon atoms; R² represents an alkylthio group having 1 to 6 carbonatoms or a hydrogen atom, wherein R² and the abovementioned R¹ may beintegrated to form a ring structure by incorporating a part of themother skeleton, the thus formed ring may contain a sulfur atom as aring-constituent atom, and the ring may be substituted by an alkyl grouphaving 1 to 6 carbon atoms, which may have a substituent; R³ representsa phenylalkyl group composed of an alkylene group having 1 to 6 carbonatoms and a phenyl group, an alkyl group having 1 to 6 carbon atoms, analkoxymethyl group having 2 to 7 carbon atoms, a hydrogen atom, a phenylgroup, an acetoxymethyl group, a pivaloyloxymethyl group, anethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a5-indanyl group, a phthalidinyl group, a5-alkyl-2-oxo-1,3-dioxole-4-ylmethyl group, or a 3-acetoxy-2-oxobutylgroup; R⁴ represents an alkyl group having 1 to 6 carbon atoms, analkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydrogenatom, an amino group, a hydroxyl group, a thiol group, or ahalogenomethyl group, and among the above, the amino group may have oneor more substituents selected from among the group consisting of analkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5carbon atoms, and a formyl group; A represents a nitrogen atom or apartial structure represented by formula (II):

 (wherein X represents an alkyl group having 1 to 6 carbon atoms, analkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydrogenatom, an amino group, a halogen atom, a cyano group, a halogenomethylgroup, or a halogenomethoxy group, among the above, the amino group mayhave one ore more substituents selected from the group consisting of analkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5carbon atoms, and a formyl group, wherein X¹ and the aforementioned R¹may be integrated to form a ring structure by incorporating a part ofthe mother skeleton, the thus formed ring may contain an oxygen atom, anitrogen atom, or a sulfur atom as a ring constituent atom, and thisring may be substituted by an alkyl group having 1 to 6 carbon atoms,which may have a substituent); each of R⁵ and R⁶ independentlyrepresents an alkyl group having 1 to 6 carbon atoms, a hydrogen atom,or a substituted carboxyl group derived from an amino acid, dipeptide,or tripeptide, wherein the alkyl group may have one ore moresubstituents selected from the group consisting of an alkylthio grouphaving 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms,a hydroxyl group, and a halogen atom; and n represents an integer 1 or2].
 2. The compound according to claim 1, its salts or hydrates thereof,wherein the compound of formula (I) is a stereochemically pure compound.3. The compound according to claim 1 or 2, its salts or hydratesthereof, wherein n in the formula (I) is
 1. 4. The compound according toany one of claims 1 to 3, its salts or hydrates thereof, wherein R³ inthe formula (I) is a hydrogen atom.
 5. The compound according to any oneof claims 1 to 4, its salts or hydrates thereof, wherein R² in theformula (I) is a hydrogen atom.
 6. The compound according to any one ofclaims 1 to 5, its salts or hydrates thereof, wherein R⁴ in the formula(I) is a hydrogen atom.
 7. The compound according to any one of claims 1to 6, its salts or hydrates thereof, wherein A in the formula (I) is apartial structure represented by the formula (II).
 8. The compoundaccording to claim 7, its salts or hydrates thereof, wherein X¹ in theformula (II) is a methoxy group, a methyl group, a difluoromethoxygroup, a fluorine atom, or a chlorine atom.
 9. The compound according toclaim 7, its salts or hydrates thereof, wherein X¹ in the formula (II)is a methoxy group or a methyl group.
 10. The compound according to anyone of claims 1 to 9, its salts or hydrates thereof, wherein each of R⁵and R⁶ in the formula (I) is a hydrogen atom.
 11. The compound accordingto any one of claims 1 to 9, its salts or hydrates thereof, wherein oneof either R⁵ or R⁶ in the formula (I) is a hydrogen atom and the otheris a methyl group.
 12. The compound according to any one of claims 1 to9, its salts or hydrates thereof, wherein one of either R⁵ or R⁶ informula (I) is a hydrogen atom and the other is a substituted carboxylgroup derived from an amino acid, a dipeptide, or a tripeptide.
 13. Thecompound according to any one of claims 1 to 12, its salts or hydratesthereof, wherein the cyclic alkyl group having 3 to 6 carbon atoms,which may have a substituent, in R¹ is a halogenocyclopropyl group. 14.The compound according to claim 13, its salts or hydrates thereof,wherein the halogenocyclopropyl group is a 1,2-cis-2-halogenocyclopropylgroup.
 15. The compound according to claim 14, its salts or hydratesthereof, wherein the halogenocyclopropyl group is a stereochemicallypure substituent.
 16. The compound according to claim 15, its salts orhydrates thereof, wherein the halogenocyclopropyl group is a (1R,2S)-2-halogenocyclopropyl group.
 17. The compound according to any oneof claims 13 to 16, its salts or hydrates thereof, wherein the halogenatom of the halogenocyclopropyl group is a fluorine atom. 18.7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, its salts or hydrates thereof. 19.7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof. 20.7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof. 21.7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof. 22.7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof. 23.7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof. 24.7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof. 25.7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof. 26.7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof. 27.7-[3-(R)-[1-(ethylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof. 28.5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-fluoro-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof. 29.5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof. 30.5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof. 31.5-amino-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof. 32.10-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylicacid, its salts or hydrates thereof. 33.1-(cyclopropyl)-8-methyl-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof.
 34. A medicament, which comprisesthe compound described in any one of claims 1 to 33, its salts orhydrates thereof as an active ingredient.
 35. An antibacterial agent,which comprises the compound described in any of claims 1 to 33, itssalts or hydrates thereof, as an active ingredient.
 36. A therapeuticagent for an infectious disease, which comprises the compound describedin any of claims 1 to 33, its salts or hydrates thereof, as an activeingredient.
 37. A method for treating a disease, which comprisesadministrating the compound described in any of claims 1 to 33, itssalts or hydrates thereof, as an active ingredient.
 38. A method fortreating an infectious disease, which comprises administrating thecompound described in any of claims 1 to 33, its salts or hydratesthereof, as an active ingredient.
 39. A method for producing amedicament, which comprises formulating the compound described in any ofclaims 1 to 33, its salts or hydrates thereof, as an active ingredient.40. A method for producing an antibacterial agent, which comprisesformulating the compound described in any of claims 1 to 33, its saltsor hydrates thereof, as an active ingredient.
 41. A method for producingan infectious disease treating agent, which comprises formulating thecompound described in any of claims 1 to 33, its salts or hydratesthereof, as an active ingredient.
 42. Use of the compound described inany of claims 1 to 33, its salts or hydrates thereof, for the productionof a medicament.
 43. Use of the compound described in any of claims 1 to33, its salts or hydrates thereof for the production of an antibacterialagent.
 44. Use of the compound described in any of claims 1 to 33, itssalts or hydrates thereof for the production of an infectious diseasetreating agent.